ID ABCA7_HUMAN Reviewed; 2146 AA. AC Q8IZY2; Q96S58; Q9BZC4; Q9NR73; Q9UKP8; DT 03-OCT-2006, integrated into UniProtKB/Swiss-Prot. DT 04-DEC-2007, sequence version 3. DT 28-JAN-2026, entry version 172. DE RecName: Full=Phospholipid-transporting ATPase ABCA7 {ECO:0000305}; DE EC=7.6.2.1 {ECO:0000269|PubMed:24097981}; DE AltName: Full=ABCA-SSN {ECO:0000303|PubMed:11355874}; DE AltName: Full=ATP-binding cassette sub-family A member 7 {ECO:0000305}; DE AltName: Full=Autoantigen SS-N {ECO:0000303|Ref.6}; DE AltName: Full=Macrophage ABC transporter {ECO:0000303|PubMed:10873640}; GN Name=ABCA7 {ECO:0000312|HGNC:HGNC:37}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS GLN-1349; ALA-1527 AND RP SER-2045, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND INDUCTION. RC TISSUE=Macrophage; RX PubMed=10873640; DOI=10.1006/bbrc.2000.2954; RA Kaminski W.E., Orso E., Diederich W., Klucken J., Drobnik W., Schmitz G.; RT "Identification of a novel human sterol-sensitive ATP-binding cassette RT transporter (ABCA7)."; RL Biochem. Biophys. Res. Commun. 273:532-538(2000). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ALA-1527. RX PubMed=11095984; DOI=10.1006/bbrc.2000.3880; RA Kaminski W.E., Piehler A., Schmitz G.; RT "Genomic organization of the human cholesterol-responsive ABC transporter RT ABCA7: tandem linkage with the minor histocompatibility antigen HA-1 RT gene."; RL Biochem. Biophys. Res. Commun. 278:782-789(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND VARIANTS GLN-1349; ALA-1527 AND RP SER-2045. RC TISSUE=Thymus; RX PubMed=11355874; DOI=10.1006/bbrc.2001.4891; RA Tanaka A.R., Ikeda Y., Abe-Dohmae S., Arakawa R., Sadanami K., Kidera A., RA Nakagawa S., Nagase T., Aoki R., Kioka N., Amachi T., Yokoyama S., Ueda K.; RT "Human ABCA1 contains a large amino-terminal extracellular domain RT homologous to an epitope of Sjogren's Syndrome."; RL Biochem. Biophys. Res. Commun. 283:1019-1025(2001). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS GLY-188; ALA-1527 AND RP SER-2045, TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE. RC TISSUE=Spleen; RX PubMed=11435699; DOI=10.1159/000056914; RA Broccardo C., Osorio J., Luciani M.-F., Schriml L.M., Prades C., RA Shulenin S., Arnould I., Naudin L., Lafargue C., Rosier M., Jordan B., RA Mattei M.-G., Dean M., Denefle P., Chimini G.; RT "Comparative analysis of the promoter structure and genomic organization of RT the human and mouse ABCA7 gene encoding a novel ABCA transporter."; RL Cytogenet. Cell Genet. 92:264-270(2001). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057824; DOI=10.1038/nature02399; RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A., RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., RA Rubin E.M., Lucas S.M.; RT "The DNA sequence and biology of human chromosome 19."; RL Nature 428:529-535(2004). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] OF 195-352 (ISOFORMS 1/2). RC TISSUE=Cervix carcinoma; RA Niwa M., Maruyama M., Fujimoto T., Dohi K., Maruyama I.N.; RT "Isolation of autoantigen cDNAs by lambda phage surface display."; RL Submitted (APR-1999) to the EMBL/GenBank/DDBJ databases. RN [7] RP FUNCTION, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=14592415; DOI=10.1016/j.bbrc.2003.10.002; RA Ikeda Y., Abe-Dohmae S., Munehira Y., Aoki R., Kawamoto S., Furuya A., RA Shitara K., Amachi T., Kioka N., Matsuo M., Yokoyama S., Ueda K.; RT "Posttranscriptional regulation of human ABCA7 and its function for the RT apoA-I-dependent lipid release."; RL Biochem. Biophys. Res. Commun. 311:313-318(2003). RN [8] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=12917409; DOI=10.1074/jbc.m307831200; RA Wang N., Lan D., Gerbod-Giannone M., Linsel-Nitschke P., Jehle A.W., RA Chen W., Martinez L.O., Tall A.R.; RT "ATP-binding cassette transporter A7 (ABCA7) binds apolipoprotein A-I and RT mediates cellular phospholipid but not cholesterol efflux."; RL J. Biol. Chem. 278:42906-42912(2003). RN [9] RP FUNCTION, AND INDUCTION. RX PubMed=12925201; DOI=10.1046/j.1523-1747.2003.12404.x; RA Kielar D., Kaminski W.E., Liebisch G., Piehler A., Wenzel J.J., Moehle C., RA Heimerl S., Langmann T., Friedrich S.O., Boettcher A., Barlage S., RA Drobnik W., Schmitz G.; RT "Adenosine triphosphate binding cassette (ABC) transporters are expressed RT and regulated during terminal keratinocyte differentiation: a potential RT role for ABCA7 in epidermal lipid reorganization."; RL J. Invest. Dermatol. 121:465-474(2003). RN [10] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=14570867; DOI=10.1074/jbc.m309888200; RA Abe-Dohmae S., Ikeda Y., Matsuo M., Hayashi M., Okuhira K., Ueda K., RA Yokoyama S.; RT "Human ABCA7 supports apolipoprotein-mediated release of cellular RT cholesterol and phospholipid to generate high density lipoprotein."; RL J. Biol. Chem. 279:604-611(2004). RN [11] RP CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND FUNCTION. RX PubMed=24097981; DOI=10.1074/jbc.m113.508812; RA Quazi F., Molday R.S.; RT "Differential phospholipid substrates and directional transport by ATP- RT binding cassette proteins ABCA1, ABCA7, and ABCA4 and disease-causing RT mutants."; RL J. Biol. Chem. 288:34414-34426(2013). RN [12] RP FUNCTION. RX PubMed=26260791; DOI=10.1074/jbc.m115.655076; RA Satoh K., Abe-Dohmae S., Yokoyama S., St George-Hyslop P., Fraser P.E.; RT "ATP-binding cassette transporter A7 (ABCA7) loss of function alters RT Alzheimer amyloid processing."; RL J. Biol. Chem. 290:24152-24165(2015). RN [13] RP INVOLVEMENT IN AD9. RX PubMed=26141617; DOI=10.1016/s1474-4422(15)00133-7; RA Cuyvers E., De Roeck A., Van den Bossche T., Van Cauwenberghe C., RA Bettens K., Vermeulen S., Mattheijssens M., Peeters K., Engelborghs S., RA Vandenbulcke M., Vandenberghe R., De Deyn P.P., Van Broeckhoven C., RA Sleegers K.; RT "Mutations in ABCA7 in a Belgian cohort of Alzheimer's disease patients: a RT targeted resequencing study."; RL Lancet Neurol. 14:814-822(2015). RN [14] RP INVOLVEMENT IN AD9. RX PubMed=25807283; DOI=10.1038/ng.3246; RG DemGene; RA Steinberg S., Stefansson H., Jonsson T., Johannsdottir H., Ingason A., RA Helgason H., Sulem P., Magnusson O.T., Gudjonsson S.A., Unnsteinsdottir U., RA Kong A., Helisalmi S., Soininen H., Lah J.J., Aarsland D., Fladby T., RA Ulstein I.D., Djurovic S., Sando S.B., White L.R., Knudsen G.P., RA Westlye L.T., Selbaek G., Giegling I., Hampel H., Hiltunen M., Levey A.I., RA Andreassen O.A., Rujescu D., Jonsson P.V., Bjornsson S., Snaedal J., RA Stefansson K.; RT "Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease."; RL Nat. Genet. 47:445-447(2015). RN [15] RP TISSUE SPECIFICITY. RX PubMed=27472885; DOI=10.3233/jad-160456; RA Fu Y., Hsiao J.H., Paxinos G., Halliday G.M., Kim W.S.; RT "ABCA7 Mediates Phagocytic Clearance of Amyloid-beta in the Brain."; RL J. Alzheimers Dis. 54:569-584(2016). RN [16] RP VARIANTS GLY-188; ALA-319; ARG-395; HIS-463; THR-718; GLN-1349; ARG-1686 RP AND SER-2045. RX PubMed=12111378; DOI=10.1007/s100380200041; RA Iida A., Saito S., Sekine A., Mishima C., Kitamura Y., Kondo K., RA Harigae S., Osawa S., Nakamura Y.; RT "Catalog of 605 single-nucleotide polymorphisms (SNPs) among 13 genes RT encoding human ATP-binding cassette transporters: ABCA4, ABCA7, ABCA8, RT ABCD1, ABCD3, ABCD4, ABCE1, ABCF1, ABCG1, ABCG2, ABCG4, ABCG5, and ABCG8."; RL J. Hum. Genet. 47:285-310(2002). RN [17] RP VARIANT AD9 GLN-880. RX PubMed=29577078; DOI=10.1212/nxg.0000000000000224; RA May P., Pichler S., Hartl D., Bobbili D.R., Mayhaus M., Spaniol C., RA Kurz A., Balling R., Schneider J.G., Riemenschneider M.; RT "Rare ABCA7 variants in 2 German families with Alzheimer disease."; RL Neurol. Genet. 4:E224-E224(2018). CC -!- FUNCTION: Catalyzes the translocation of specific phospholipids from CC the cytoplasmic to the extracellular/lumenal leaflet of membrane CC coupled to the hydrolysis of ATP (PubMed:24097981). Transports CC preferentially phosphatidylserine over phosphatidylcholine CC (PubMed:24097981). Plays a role in lipid homeostasis and macrophage- CC mediated phagocytosis (PubMed:12917409, PubMed:12925201, CC PubMed:14570867, PubMed:14592415). Binds APOA1 and may function in CC apolipoprotein-mediated phospholipid efflux from cells CC (PubMed:12917409, PubMed:14570867, PubMed:14592415). May also mediate CC cholesterol efflux (PubMed:14570867). May regulate cellular ceramide CC homeostasis during keratinocyte differentiation (PubMed:12925201). CC Involved in lipid raft organization and CD1D localization on thymocytes CC and antigen-presenting cells, which plays an important role in natural CC killer T-cell development and activation (By similarity). Plays a role CC in phagocytosis of apoptotic cells by macrophages (By similarity). CC Macrophage phagocytosis is stimulated by APOA1 or APOA2, probably by CC stabilization of ABCA7 (By similarity). Also involved in phagocytic CC clearance of amyloid-beta by microglia cells and macrophages (By CC similarity). Further limits amyloid-beta production by playing a role CC in the regulation of amyloid-beta A4 precursor protein (APP) CC endocytosis and/or processing (PubMed:26260791). Amyloid-beta is the CC main component of amyloid plaques found in the brains of Alzheimer CC patients (PubMed:26260791). {ECO:0000250|UniProtKB:Q91V24, CC ECO:0000269|PubMed:12917409, ECO:0000269|PubMed:12925201, CC ECO:0000269|PubMed:14570867, ECO:0000269|PubMed:14592415, CC ECO:0000269|PubMed:24097981, ECO:0000269|PubMed:26260791}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + H2O + phospholipidSide 1 = ADP + phosphate + CC phospholipidSide 2.; EC=7.6.2.1; CC Evidence={ECO:0000269|PubMed:24097981}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 1,2-diacyl-sn-glycero-3-phosphocholine(out) + ATP + H2O = a CC 1,2-diacyl-sn-glycero-3-phosphocholine(in) + ADP + phosphate + H(+); CC Xref=Rhea:RHEA:38583, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:57643, CC ChEBI:CHEBI:456216; Evidence={ECO:0000269|PubMed:24097981}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38584; CC Evidence={ECO:0000305|PubMed:24097981}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-L-serine(out) + ATP + H2O = CC a 1,2-diacyl-sn-glycero-3-phospho-L-serine(in) + ADP + phosphate + CC H(+); Xref=Rhea:RHEA:38567, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:57262, CC ChEBI:CHEBI:456216; Evidence={ECO:0000269|PubMed:24097981}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38568; CC Evidence={ECO:0000305|PubMed:24097981}; CC -!- ACTIVITY REGULATION: ATPase activity is decreased by cholesterol and CC ceramide. ATPase activity is stimulated by phosphatidylserine, CC phosphatidylcholine and sphingomyelin, but phosphatidylserine is more CC effective. {ECO:0000269|PubMed:24097981}. CC -!- INTERACTION: CC Q8IZY2; Q14160: SCRIB; NbExp=2; IntAct=EBI-2838910, EBI-357345; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:12917409, CC ECO:0000269|PubMed:14592415}; Multi-pass membrane protein CC {ECO:0000255}. Golgi apparatus membrane {ECO:0000250|UniProtKB:Q91V24}; CC Multi-pass membrane protein {ECO:0000255}. Early endosome membrane CC {ECO:0000250|UniProtKB:Q91V24}; Multi-pass membrane protein CC {ECO:0000255}. Cytoplasm {ECO:0000250|UniProtKB:Q91V24}. Cell CC projection, ruffle membrane {ECO:0000250|UniProtKB:Q91V24}. Cell CC projection, phagocytic cup {ECO:0000250|UniProtKB:Q91V24}. CC Note=Localizes to cell membrane ruffles and phagocytic cups of CC macrophages stimulated with C1q or apoptotic cells. Localizes to the CC cytoplasm of resting macrophages, probably in Golgi and endosomes. CC Localizes to the apical brush border of cells in the proximal tubules CC of kidney (By similarity). {ECO:0000250|UniProtKB:Q91V24}. CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm CC {ECO:0000269|PubMed:14592415}. Endoplasmic reticulum CC {ECO:0000269|PubMed:14592415}. Note=May localize to the endoplasmic CC reticulum. {ECO:0000269|PubMed:14592415}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; Synonyms=Type 1; CC IsoId=Q8IZY2-1; Sequence=Displayed; CC Name=2; Synonyms=Type 2; CC IsoId=Q8IZY2-2; Sequence=VSP_020701, VSP_020702; CC -!- TISSUE SPECIFICITY: Expressed in leukocytes (at protein level) CC (PubMed:10873640). Widely expressed (PubMed:10873640). Highly expressed CC in myelo-lymphatic tissues including peripheral leukocytes, thymus, CC spleen and bone marrow (PubMed:10873640, PubMed:11435699). Expressed in CC the hippocampus and the cerebellum (PubMed:27472885). Isoform 2: CC Abundant in lymph node, spleen, thymus and trachea (PubMed:14592415). CC Isoform 1: Strongly expressed in brain and bone marrow CC (PubMed:14592415). {ECO:0000269|PubMed:10873640, CC ECO:0000269|PubMed:11435699, ECO:0000269|PubMed:14592415, CC ECO:0000269|PubMed:27472885}. CC -!- DEVELOPMENTAL STAGE: Expressed in fetal tissues. Strongly expressed in CC fetal liver. {ECO:0000269|PubMed:10873640, CC ECO:0000269|PubMed:11435699}. CC -!- INDUCTION: Up-regulated in macrophages upon cholesterol uptake and CC inversely regulated upon cholesterol deloading from the cells (at CC protein level). Up-regulated in keratinocytes during terminal CC differentiation. {ECO:0000269|PubMed:10873640, CC ECO:0000269|PubMed:12925201}. CC -!- PTM: N-glycosylated. {ECO:0000250|UniProtKB:Q91V24}. CC -!- DISEASE: Alzheimer disease 9 (AD9) [MIM:608907]: A familial, late-onset CC form of Alzheimer disease. Alzheimer disease is a neurodegenerative CC disorder characterized by progressive dementia, loss of cognitive CC abilities, and deposition of fibrillar amyloid proteins as CC intraneuronal neurofibrillary tangles, extracellular amyloid plaques CC and vascular amyloid deposits. The major constituents of these plaques CC are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, CC that are produced by the proteolysis of the transmembrane APP protein. CC The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved CC products, such as C31, are also implicated in neuronal death. CC {ECO:0000269|PubMed:25807283, ECO:0000269|PubMed:26141617, CC ECO:0000269|PubMed:29577078}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 2]: Inactive for apoA-I-mediated lipid release. CC {ECO:0000305}. CC -!- SIMILARITY: Belongs to the ABC transporter superfamily. ABCA family. CC {ECO:0000305}. CC -!- CAUTION: There are conflicting results concerning the role of ABCA7 in CC lipid transport. ABCA7 was described to play a role in apolipoprotein- CC mediated phospholipid and cholesterol efflux when expressed in HEK293 CC cells (PubMed:12917409, PubMed:27472885). However, another report shows CC that ABCA7 deficiency does not influence cholesterol and phospholipid CC efflux in mouse primary macrophages, but leads to lower serum HDL CC cholesterol levels and a reduction in fat mass in female mice (By CC similarity). {ECO:0000250|UniProtKB:Q91V24, CC ECO:0000269|PubMed:12917409, ECO:0000269|PubMed:27472885}. CC -!- WEB RESOURCE: Name=ABCMdb; Note=Database for mutations in ABC proteins; CC URL="http://abcm2.hegelab.org/search"; 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; AF250238; AAF85794.1; -; mRNA. DR EMBL; AF311102; AAN04657.1; -; Genomic_DNA. DR EMBL; AF311058; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311059; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311060; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311061; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311062; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311063; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311064; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311065; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311066; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311067; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311068; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311057; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311069; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311070; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311071; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311072; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311073; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311074; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311075; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311076; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311077; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311078; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311079; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311080; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311081; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311082; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311083; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311084; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311085; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311086; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311087; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311088; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311089; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311090; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311091; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311092; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311093; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311094; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311095; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311096; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311097; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311098; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311099; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311100; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AF311101; AAN04657.1; JOINED; Genomic_DNA. DR EMBL; AB055390; BAB62294.1; -; mRNA. DR EMBL; AF328787; AAK00959.1; -; mRNA. DR EMBL; AC011558; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AF140342; AAF06727.1; -; mRNA. DR CCDS; CCDS12055.1; -. [Q8IZY2-1] DR RefSeq; NP_061985.2; NM_019112.4. [Q8IZY2-1] DR RefSeq; XP_047294000.1; XM_047438044.1. [Q8IZY2-1] DR PDB; 8EDW; EM; 3.60 A; A=1-2146. DR PDB; 8EE6; EM; 4.00 A; A=1-2146. DR PDB; 8EEB; EM; 3.90 A; A=1-2146. DR PDB; 8EOP; EM; 3.70 A; A=1-2146. DR PDB; 8Y1O; EM; 3.92 A; A=1-2146. DR PDB; 8Y1P; EM; 3.45 A; A=1-2146. DR PDBsum; 8EDW; -. DR PDBsum; 8EE6; -. DR PDBsum; 8EEB; -. DR PDBsum; 8EOP; -. DR PDBsum; 8Y1O; -. DR PDBsum; 8Y1P; -. DR AlphaFoldDB; Q8IZY2; -. DR EMDB; EMD-28041; -. DR EMDB; EMD-28047; -. DR EMDB; EMD-28050; -. DR EMDB; EMD-28451; -. DR EMDB; EMD-38841; -. DR EMDB; EMD-38842; -. DR SMR; Q8IZY2; -. DR BioGRID; 115629; 24. DR FunCoup; Q8IZY2; 325. DR IntAct; Q8IZY2; 47. DR MINT; Q8IZY2; -. DR STRING; 9606.ENSP00000263094; -. DR SwissLipids; SLP:000000346; -. DR TCDB; 3.A.1.211.10; the atp-binding cassette (abc) superfamily. DR GlyConnect; 1022; 1 N-Linked glycan (1 site). DR GlyCosmos; Q8IZY2; 3 sites, 2 glycans. DR GlyGen; Q8IZY2; 10 sites, 4 N-linked glycans (6 sites), 1 O-linked glycan (1 site). DR iPTMnet; Q8IZY2; -. DR PhosphoSitePlus; Q8IZY2; -. DR SwissPalm; Q8IZY2; -. DR BioMuta; ABCA7; -. DR DMDM; 161784300; -. DR jPOST; Q8IZY2; -. DR MassIVE; Q8IZY2; -. DR PaxDb; 9606-ENSP00000263094; -. DR PeptideAtlas; Q8IZY2; -. DR ProteomicsDB; 71441; -. [Q8IZY2-1] DR ProteomicsDB; 71442; -. [Q8IZY2-2] DR Antibodypedia; 22516; 184 antibodies from 31 providers. DR DNASU; 10347; -. DR Ensembl; ENST00000263094.11; ENSP00000263094.6; ENSG00000064687.13. [Q8IZY2-1] DR GeneID; 10347; -. DR KEGG; hsa:10347; -. DR MANE-Select; ENST00000263094.11; ENSP00000263094.6; NM_019112.4; NP_061985.2. DR UCSC; uc002lqw.5; human. [Q8IZY2-1] DR AGR; HGNC:37; -. DR ClinPGx; PA24382; -. DR CTD; 10347; -. DR DisGeNET; 10347; -. DR GeneCards; ABCA7; -. DR HGNC; HGNC:37; ABCA7. DR HPA; ENSG00000064687; Tissue enhanced (pituitary). DR MalaCards; ABCA7; -. DR MIM; 605414; gene. DR MIM; 608907; phenotype. DR NIAGADS; ENSG00000064687; -. DR OpenTargets; ENSG00000064687; -. DR VEuPathDB; HostDB:ENSG00000064687; -. DR eggNOG; KOG0059; Eukaryota. DR GeneTree; ENSGT00940000161439; -. DR HOGENOM; CLU_000604_19_0_1; -. DR InParanoid; Q8IZY2; -. DR OMA; LVSYIKF; -. DR OrthoDB; 8061355at2759; -. DR PAN-GO; Q8IZY2; 7 GO annotations based on evolutionary models. DR PhylomeDB; Q8IZY2; -. DR PathwayCommons; Q8IZY2; -. DR Reactome; R-HSA-1369062; ABC transporters in lipid homeostasis. DR SignaLink; Q8IZY2; -. DR SIGNOR; Q8IZY2; -. DR Agora; ENSG00000064687; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 10347; 22 hits in 1162 CRISPR screens. DR ChiTaRS; ABCA7; human. DR GeneWiki; ABCA7; -. DR GenomeRNAi; 10347; -. DR Pharos; Q8IZY2; Tbio. DR PRO; PR:Q8IZY2; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; Q8IZY2; protein. DR Bgee; ENSG00000064687; Expressed in granulocyte and 145 other cell types or tissues. DR ExpressionAtlas; Q8IZY2; baseline and differential. DR GO; GO:0030054; C:cell junction; IDA:HPA. DR GO; GO:0009986; C:cell surface; ISS:Alzheimers_University_of_Toronto. DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell. DR GO; GO:0097386; C:glial cell projection; ISS:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0001891; C:phagocytic cup; ISS:Alzheimers_University_of_Toronto. DR GO; GO:0005886; C:plasma membrane; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0032587; C:ruffle membrane; ISS:Alzheimers_University_of_Toronto. DR GO; GO:0140359; F:ABC-type transporter activity; IEA:InterPro. DR GO; GO:0034188; F:apolipoprotein A-I receptor activity; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0016887; F:ATP hydrolysis activity; IEA:InterPro. DR GO; GO:0042626; F:ATPase-coupled transmembrane transporter activity; IBA:GO_Central. DR GO; GO:0140328; F:floppase activity; IDA:UniProtKB. DR GO; GO:0090554; F:phosphatidylcholine floppase activity; IDA:BHF-UCL. DR GO; GO:0090556; F:phosphatidylserine floppase activity; IDA:BHF-UCL. DR GO; GO:0005548; F:phospholipid transporter activity; IGI:ARUK-UCL. DR GO; GO:0150094; P:amyloid-beta clearance by cellular catabolic process; ISS:UniProtKB. DR GO; GO:0034205; P:amyloid-beta formation; IMP:UniProtKB. DR GO; GO:0038027; P:apolipoprotein A-I-mediated signaling pathway; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0033344; P:cholesterol efflux; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0034380; P:high-density lipoprotein particle assembly; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0007613; P:memory; ISS:Alzheimers_University_of_Toronto. DR GO; GO:0042985; P:negative regulation of amyloid precursor protein biosynthetic process; ISS:Alzheimers_University_of_Toronto. DR GO; GO:1902430; P:negative regulation of amyloid-beta formation; ISS:Alzheimers_University_of_Toronto. DR GO; GO:0045806; P:negative regulation of endocytosis; ISS:UniProtKB. DR GO; GO:0043409; P:negative regulation of MAPK cascade; ISS:ARUK-UCL. DR GO; GO:1903898; P:negative regulation of PERK-mediated unfolded protein response; ISS:ARUK-UCL. DR GO; GO:0006909; P:phagocytosis; IEA:UniProtKB-KW. DR GO; GO:0033700; P:phospholipid efflux; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0045332; P:phospholipid translocation; IDA:BHF-UCL. DR GO; GO:0044857; P:plasma membrane raft organization; ISS:UniProtKB. DR GO; GO:1900223; P:positive regulation of amyloid-beta clearance; ISS:Alzheimers_University_of_Toronto. DR GO; GO:0010875; P:positive regulation of cholesterol efflux; ISS:Alzheimers_University_of_Toronto. DR GO; GO:1901076; P:positive regulation of engulfment of apoptotic cell; ISS:Alzheimers_University_of_Toronto. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:Alzheimers_University_of_Toronto. DR GO; GO:0050766; P:positive regulation of phagocytosis; ISS:Alzheimers_University_of_Toronto. DR GO; GO:1902995; P:positive regulation of phospholipid efflux; ISS:Alzheimers_University_of_Toronto. DR GO; GO:2000010; P:positive regulation of protein localization to cell surface; ISS:UniProtKB. DR GO; GO:0034504; P:protein localization to nucleus; ISS:Alzheimers_University_of_Toronto. DR GO; GO:1902991; P:regulation of amyloid precursor protein catabolic process; IMP:UniProtKB. DR GO; GO:0019216; P:regulation of lipid metabolic process; ISS:ARUK-UCL. DR GO; GO:0008542; P:visual learning; ISS:ARUK-UCL. DR CDD; cd03263; ABC_subfamily_A; 2. DR FunFam; 3.40.50.300:FF:001235; ATP binding cassette subfamily A member 7; 1. DR FunFam; 3.40.50.300:FF:000511; ATP-binding cassette, sub-family A (ABC1), member 2; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 2. DR InterPro; IPR003593; AAA+_ATPase. DR InterPro; IPR013525; ABC2_TM. DR InterPro; IPR003439; ABC_transporter-like_ATP-bd. DR InterPro; IPR017871; ABC_transporter-like_CS. DR InterPro; IPR026082; ABCA. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR056264; R2_ABCA1-4-like. DR PANTHER; PTHR19229; ATP-BINDING CASSETTE TRANSPORTER SUBFAMILY A ABCA; 1. DR PANTHER; PTHR19229:SF49; PHOSPHOLIPID-TRANSPORTING ATPASE ABCA7; 1. DR Pfam; PF12698; ABC2_membrane_3; 2. DR Pfam; PF00005; ABC_tran; 2. DR Pfam; PF23321; R1_ABCA1; 1. DR SMART; SM00382; AAA; 2. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 2. DR PROSITE; PS00211; ABC_TRANSPORTER_1; 1. DR PROSITE; PS50893; ABC_TRANSPORTER_2; 2. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Alzheimer disease; Amyloidosis; KW ATP-binding; Cell membrane; Cell projection; Cytoplasm; Disulfide bond; KW Endoplasmic reticulum; Endosome; Glycoprotein; Golgi apparatus; KW Lipid transport; Membrane; Neurodegeneration; Nucleotide-binding; KW Phagocytosis; Proteomics identification; Reference proteome; Repeat; KW Translocase; Transmembrane; Transmembrane helix; Transport. FT CHAIN 1..2146 FT /note="Phospholipid-transporting ATPase ABCA7" FT /id="PRO_0000250674" FT TRANSMEM 22..42 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 43..549 FT /note="Extracellular" FT /evidence="ECO:0000250" FT TRANSMEM 550..570 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 593..613 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 626..646 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 655..675 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 687..707 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 727..747 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 849..869 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 1243..1263 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1264..1537 FT /note="Extracellular" FT /evidence="ECO:0000250" FT TRANSMEM 1538..1558 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 1584..1604 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 1621..1641 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 1649..1669 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 1683..1703 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 1729..1749 FT /note="Helical" FT /evidence="ECO:0000255" FT DOMAIN 807..1038 FT /note="ABC transporter 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434" FT DOMAIN 1793..2025 FT /note="ABC transporter 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434" FT REGION 1048..1072 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1185..1209 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 2104..2146 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1048..1066 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 841..848 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434" FT BINDING 1827..1834 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434" FT CARBOHYD 312 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 75..225 FT /evidence="ECO:0000250" FT DISULFID 1345..1359 FT /evidence="ECO:0000250" FT VAR_SEQ 1..138 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:11355874" FT /id="VSP_020701" FT VAR_SEQ 139..166 FT /note="AQPQPTKQSPLEPPMLDVAELLTSLLRT -> MVCLGTGQSAGPLVSVQNHC FT PPCGLSPQ (in isoform 2)" FT /evidence="ECO:0000303|PubMed:11355874" FT /id="VSP_020702" FT VARIANT 188 FT /note="E -> G (in dbSNP:rs3764645)" FT /evidence="ECO:0000269|PubMed:11435699, FT ECO:0000269|PubMed:12111378" FT /id="VAR_027581" FT VARIANT 319 FT /note="T -> A (in dbSNP:rs3752232)" FT /evidence="ECO:0000269|PubMed:12111378" FT /id="VAR_027582" FT VARIANT 395 FT /note="H -> R (in dbSNP:rs3764647)" FT /evidence="ECO:0000269|PubMed:12111378" FT /id="VAR_027583" FT VARIANT 463 FT /note="R -> H (in dbSNP:rs3752233)" FT /evidence="ECO:0000269|PubMed:12111378" FT /id="VAR_027584" FT VARIANT 676 FT /note="A -> T (in dbSNP:rs59851484)" FT /id="VAR_060985" FT VARIANT 718 FT /note="N -> T (in dbSNP:rs3752239)" FT /evidence="ECO:0000269|PubMed:12111378" FT /id="VAR_027585" FT VARIANT 880 FT /note="R -> Q (in AD9; dbSNP:rs143718918)" FT /evidence="ECO:0000269|PubMed:29577078" FT /id="VAR_081204" FT VARIANT 1349 FT /note="R -> Q (in dbSNP:rs3745842)" FT /evidence="ECO:0000269|PubMed:10873640, FT ECO:0000269|PubMed:11355874, ECO:0000269|PubMed:12111378" FT /id="VAR_027586" FT VARIANT 1527 FT /note="G -> A (in dbSNP:rs3752246)" FT /evidence="ECO:0000269|PubMed:10873640, FT ECO:0000269|PubMed:11095984, ECO:0000269|PubMed:11355874, FT ECO:0000269|PubMed:11435699" FT /id="VAR_027587" FT VARIANT 1686 FT /note="Q -> R (in dbSNP:rs4147918)" FT /evidence="ECO:0000269|PubMed:12111378" FT /id="VAR_027588" FT VARIANT 2045 FT /note="A -> S (in dbSNP:rs4147934)" FT /evidence="ECO:0000269|PubMed:10873640, FT ECO:0000269|PubMed:11355874, ECO:0000269|PubMed:11435699, FT ECO:0000269|PubMed:12111378" FT /id="VAR_027589" FT CONFLICT 1503 FT /note="P -> R (in Ref. 1; AAF85794 and 3; BAB62294)" FT /evidence="ECO:0000305" FT CONFLICT 1525 FT /note="S -> F (in Ref. 1; AAF85794, 2; AAN04657 and 3; FT BAB62294)" FT /evidence="ECO:0000305" FT HELIX 3..19 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 24..30 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 31..33 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 36..38 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 39..43 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 49..51 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 62..64 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 67..74 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 82..84 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 89..92 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 101..113 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 116..125 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 126..129 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 130..132 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 177..193 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 200..207 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 216..219 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 220..223 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 265..274 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 278..291 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 294..297 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 302..316 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 317..320 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 323..336 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 338..341 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 342..346 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 348..351 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 377..382 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 387..389 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 390..399 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 404..406 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 412..414 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 418..429 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 430..432 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 434..438 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 462..467 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 470..473 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 492..495 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 497..500 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 503..519 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 528..531 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 537..539 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 541..544 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 547..549 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 552..555 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 556..558 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 559..574 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 579..582 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 583..585 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 589..599 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 602..605 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 608..610 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 611..616 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 625..632 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 635..639 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 640..643 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 645..647 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 653..656 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 657..665 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 666..668 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 669..675 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 683..686 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 687..692 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 693..696 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 698..704 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 705..708 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 710..712 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 718..721 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 723..727 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 730..742 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 748..754 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 758..760 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 843..846 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 847..854 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 862..864 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 876..879 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 880..882 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 898..907 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 913..916 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 917..926 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 931..934 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 944..948 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 951..953 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 955..957 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 959..962 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 966..969 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 972..984 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 985..988 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 989..991 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 998..1003 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1009..1012 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1015..1018 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1022..1029 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1034..1038 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1075..1082 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 1083..1085 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1090..1094 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1099..1102 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 1105..1107 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1108..1110 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 1111..1113 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1114..1121 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 1122..1128 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1131..1135 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1139..1150 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 1216..1219 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1221..1234 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1236..1238 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 1241..1243 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1244..1256 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1278..1283 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1293..1304 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 1312..1315 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1325..1331 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1354..1356 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1374..1381 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1387..1393 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1395..1398 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1401..1403 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1415..1418 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1431..1439 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 1440..1442 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1445..1451 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1452..1463 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1472..1475 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1477..1479 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1482..1495 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1510..1514 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1521..1531 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1534..1548 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1550..1558 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1561..1564 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1565..1569 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1576..1604 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1612..1618 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1619..1630 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1632..1637 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1638..1641 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1648..1666 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1675..1677 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1678..1688 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 1689..1692 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 1694..1696 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1698..1718 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 1729..1732 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1733..1739 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1743..1754 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1823..1825 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1830..1833 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1834..1841 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 1858..1860 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1862..1867 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1885..1892 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1901..1912 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1914..1916 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1924..1928 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1929..1939 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1958..1971 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 1986..1990 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 1994..1996 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 2009..2015 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 2020..2025 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 2028..2041 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 2046..2051 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 2054..2059 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 2063..2065 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 2066..2069 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 2070..2076 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 2079..2082 FT /evidence="ECO:0007829|PDB:8Y1P" FT STRAND 2085..2090 FT /evidence="ECO:0007829|PDB:8Y1P" FT TURN 2093..2096 FT /evidence="ECO:0007829|PDB:8Y1P" FT HELIX 2097..2101 FT /evidence="ECO:0007829|PDB:8Y1P" SQ SEQUENCE 2146 AA; 234350 MW; 6EA624088E74FEE6 CRC64; MAFWTQLMLL LWKNFMYRRR QPVQLLVELL WPLFLFFILV AVRHSHPPLE HHECHFPNKP LPSAGTVPWL QGLICNVNNT CFPQLTPGEE PGRLSNFNDS LVSRLLADAR TVLGGASAHR TLAGLGKLIA TLRAARSTAQ PQPTKQSPLE PPMLDVAELL TSLLRTESLG LALGQAQEPL HSLLEAAEDL AQELLALRSL VELRALLQRP RGTSGPLELL SEALCSVRGP SSTVGPSLNW YEASDLMELV GQEPESALPD SSLSPACSEL IGALDSHPLS RLLWRRLKPL ILGKLLFAPD TPFTRKLMAQ VNRTFEELTL LRDVREVWEM LGPRIFTFMN DSSNVAMLQR LLQMQDEGRR QPRPGGRDHM EALRSFLDPG SGGYSWQDAH ADVGHLVGTL GRVTECLSLD KLEAAPSEAA LVSRALQLLA EHRFWAGVVF LGPEDSSDPT EHPTPDLGPG HVRIKIRMDI DVVTRTNKIR DRFWDPGPAA DPLTDLRYVW GGFVYLQDLV ERAAVRVLSG ANPRAGLYLQ QMPYPCYVDD VFLRVLSRSL PLFLTLAWIY SVTLTVKAVV REKETRLRDT MRAMGLSRAV LWLGWFLSCL GPFLLSAALL VLVLKLGDIL PYSHPGVVFL FLAAFAVATV TQSFLLSAFF SRANLAAACG GLAYFSLYLP YVLCVAWRDR LPAGGRVAAS LLSPVAFGFG CESLALLEEQ GEGAQWHNVG TRPTADVFSL AQVSGLLLLD AALYGLATWY LEAVCPGQYG IPEPWNFPFR RSYWCGPRPP KSPAPCPTPL DPKVLVEEAP PGLSPGVSVR SLEKRFPGSP QPALRGLSLD FYQGHITAFL GHNGAGKTTT LSILSGLFPP SGGSAFILGH DVRSSMAAIR PHLGVCPQYN VLFDMLTVDE HVWFYGRLKG LSAAVVGPEQ DRLLQDVGLV SKQSVQTRHL SGGMQRKLSV AIAFVGGSQV VILDEPTAGV DPASRRGIWE LLLKYREGRT LILSTHHLDE AELLGDRVAV VAGGRLCCCG SPLFLRRHLG SGYYLTLVKA RLPLTTNEKA DTDMEGSVDT RQEKKNGSQG SRVGTPQLLA LVQHWVPGAR LVEELPHELV LVLPYTGAHD GSFATLFREL DTRLAELRLT GYGISDTSLE EIFLKVVEEC AADTDMEDGS CGQHLCTGIA GLDVTLRLKM PPQETALENG EPAGSAPETD QGSGPDAVGR VQGWALTRQQ LQALLLKRFL LARRSRRGLF AQIVLPALFV GLALVFSLIV PPFGHYPALR LSPTMYGAQV SFFSEDAPGD PGRARLLEAL LQEAGLEEPP VQHSSHRFSA PEVPAEVAKV LASGNWTPES PSPACQCSRP GARRLLPDCP AAAGGPPPPQ AVTGSGEVVQ NLTGRNLSDF LVKTYPRLVR QGLKTKKWVN EVRYGGFSLG GRDPGLPSGQ ELGRSVEELW ALLSPLPGGA LDRVLKNLTA WAHSLDAQDS LKIWFNNKGW HSMVAFVNRA SNAILRAHLP PGPARHAHSI TTLNHPLNLT KEQLSEGALM ASSVDVLVSI CVVFAMSFVP ASFTLVLIEE RVTRAKHLQL MGGLSPTLYW LGNFLWDMCN YLVPACIVVL IFLAFQQRAY VAPANLPALL LLLLLYGWSI TPLMYPASFF FSVPSTAYVV LTCINLFIGI NGSMATFVLE LFSDQKLQEV SRILKQVFLI FPHFCLGRGL IDMVRNQAMA DAFERLGDRQ FQSPLRWEVV GKNLLAMVIQ GPLFLLFTLL LQHRSQLLPQ PRVRSLPLLG EEDEDVARER ERVVQGATQG DVLVLRNLTK VYRGQRMPAV DRLCLGIPPG ECFGLLGVNG AGKTSTFRMV TGDTLASRGE AVLAGHSVAR EPSAAHLSMG YCPQSDAIFE LLTGREHLEL LARLRGVPEA QVAQTAGSGL ARLGLSWYAD RPAGTYSGGN KRKLATALAL VGDPAVVFLD EPTTGMDPSA RRFLWNSLLA VVREGRSVML TSHSMEECEA LCSRLAIMVN GRFRCLGSPQ HLKGRFAAGH TLTLRVPAAR SQPAAAFVAA EFPGAELREA HGGRLRFQLP PGGRCALARV FGELAVHGAE HGVEDFSVSQ TMLEEVFLYF SKDQGKDEDT EEQKEAGVGV DPAPGLQHPK RVSQFLDDPS TAETVL // ID ADA10_HUMAN Reviewed; 748 AA. AC O14672; B4DU28; Q10742; Q92650; DT 28-FEB-2003, integrated into UniProtKB/Swiss-Prot. DT 01-JAN-1998, sequence version 1. DT 28-JAN-2026, entry version 231. DE RecName: Full=Disintegrin and metalloproteinase domain-containing protein 10 {ECO:0000305}; DE Short=ADAM 10; DE EC=3.4.24.81 {ECO:0000269|PubMed:11477090, ECO:0000269|PubMed:12475894, ECO:0000269|PubMed:16239146, ECO:0000269|PubMed:17557115, ECO:0000269|PubMed:19114711, ECO:0000269|PubMed:20592283, ECO:0000269|PubMed:29224781}; DE AltName: Full=CDw156; DE AltName: Full=Kuzbanian protein homolog; DE AltName: Full=Mammalian disintegrin-metalloprotease; DE AltName: CD_antigen=CD156c; DE Flags: Precursor; GN Name=ADAM10 {ECO:0000312|HGNC:HGNC:188}; Synonyms=KUZ, MADM; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PROTEIN SEQUENCE OF 216-237. RX PubMed=9305925; DOI=10.1074/jbc.272.39.24588; RA Rosendahl M.S., Ko S.C., Long D.L., Brewer M.T., Rosenzweig B., Hedl E., RA Anderson L., Pyle S.M., Moreland J., Meyers M.A., Kohno T., Lyons D., RA Lichenstein H.S.; RT "Identification and characterization of a pro-tumor necrosis factor-alpha- RT processing enzyme from the ADAM family of zinc metalloproteases."; RL J. Biol. Chem. 272:24588-24593(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] OF 109-748 (ISOFORM 1). RX PubMed=8694785; DOI=10.1042/bj3170045; RA Howard L., Mitchell S., Lu X., Griffiths S., Glynn P.; RT "Molecular cloning of MADM: a catalytically active mammalian disintegrin- RT metalloprotease expressed in various cell types."; RL Biochem. J. 317:45-50(1996). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16572171; DOI=10.1038/nature04601; RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K., RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K., RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N., RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S., RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K., RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J., RA Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E., RA Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B., RA Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R., RA O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B., RA Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S., RA Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.; RT "Analysis of the DNA sequence and duplication history of human chromosome RT 15."; RL Nature 440:671-675(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Placenta; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP TISSUE SPECIFICITY. RX PubMed=9016778; DOI=10.1006/bbrc.1996.5957; RA McKie N., Edwards T., Dallas D.J., Houghton A., Stringer B., Graham R., RA Russell G., Croucher P.I.; RT "Expression of members of a novel membrane linked metalloproteinase family RT (ADAM) in human articular chondrocytes."; RL Biochem. Biophys. Res. Commun. 230:335-339(1997). RN [6] RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION. RX PubMed=12475894; DOI=10.1096/fj.02-0430fje; RA Gutwein P., Mechtersheimer S., Riedle S., Stoeck A., Gast D., Joumaa S., RA Zentgraf H., Fogel M., Altevogt P.; RT "ADAM10-mediated cleavage of L1 adhesion molecule at the cell surface and RT in released membrane vesicles."; RL FASEB J. 17:292-294(2003). RN [7] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=11477090; DOI=10.1074/jbc.m105677200; RA Vincent B., Paitel E., Saftig P., Frobert Y., Hartmann D., De Strooper B., RA Grassi J., Lopez-Perez E., Checler F.; RT "The disintegrins ADAM10 and TACE contribute to the constitutive and RT phorbol ester-regulated normal cleavage of the cellular prion protein."; RL J. Biol. Chem. 276:37743-37746(2001). RN [8] RP TISSUE SPECIFICITY. RX PubMed=11511685; DOI=10.1177/002215540104900910; RA Chubinskaya S., Mikhail R., Deutsch A., Tindal M.H.; RT "ADAM-10 protein is present in human articular cartilage primarily in the RT membrane-bound form and is upregulated in osteoarthritis and in response to RT IL-1alpha in bovine nasal cartilage."; RL J. Histochem. Cytochem. 49:1165-1176(2001). RN [9] RP FUNCTION. RX PubMed=11786905; DOI=10.1038/nm0102-41; RA Lemjabbar H., Basbaum C.; RT "Platelet-activating factor receptor and ADAM10 mediate responses to RT Staphylococcus aureus in epithelial cells."; RL Nat. Med. 8:41-46(2002). RN [10] RP IDENTIFICATION IN A COMPLEX WITH EFNA5 AND EPHA3, FUNCTION IN EFNA5-EPHA3 RP SIGNALING, AND CATALYTIC ACTIVITY. RX PubMed=16239146; DOI=10.1016/j.cell.2005.08.014; RA Janes P.W., Saha N., Barton W.A., Kolev M.V., Wimmer-Kleikamp S.H., RA Nievergall E., Blobel C.P., Himanen J.P., Lackmann M., Nikolov D.B.; RT "Adam meets Eph: an ADAM substrate recognition module acts as a molecular RT switch for ephrin cleavage in trans."; RL Cell 123:291-304(2005). RN [11] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-278. RC TISSUE=Platelet; RX PubMed=16263699; DOI=10.1074/mcp.m500324-mcp200; RA Lewandrowski U., Moebius J., Walter U., Sickmann A.; RT "Elucidation of N-glycosylation sites on human platelet proteins: a RT glycoproteomic approach."; RL Mol. Cell. Proteomics 5:226-233(2006). RN [12] RP FUNCTION IN CLEAVAGE OF FASLG. RX PubMed=17557115; DOI=10.1038/sj.cdd.4402175; RA Kirkin V., Cahuzac N., Guardiola-Serrano F., Huault S., Luckerath K., RA Friedmann E., Novac N., Wels W.S., Martoglio B., Hueber A.O., Zornig M.; RT "The Fas ligand intracellular domain is released by ADAM10 and SPPL2a RT cleavage in T-cells."; RL Cell Death Differ. 14:1678-1687(2007). RN [13] RP FUNCTION IN CLEAVAGE OF ITM2B. RX PubMed=19114711; DOI=10.1074/jbc.m807485200; RA Martin L., Fluhrer R., Haass C.; RT "Substrate requirements for SPPL2b-dependent regulated intramembrane RT proteolysis."; RL J. Biol. Chem. 284:5662-5670(2009). RN [14] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-278. 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 [15] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-278. RC TISSUE=Leukemic T-cell; RX PubMed=19349973; DOI=10.1038/nbt.1532; RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M., RA Schiess R., Aebersold R., Watts J.D.; RT "Mass-spectrometric identification and relative quantification of N-linked RT cell surface glycoproteins."; RL Nat. Biotechnol. 27:378-386(2009). RN [16] RP INTERACTION WITH NGF. RX PubMed=20164177; DOI=10.1074/jbc.m110.100479; RA Wijeyewickrema L.C., Gardiner E.E., Gladigau E.L., Berndt M.C., RA Andrews R.K.; RT "Nerve growth factor inhibits metalloproteinase-disintegrins and blocks RT ectodomain shedding of platelet glycoprotein VI."; RL J. Biol. Chem. 285:11793-11799(2010). RN [17] RP FUNCTION IN CLEAVAGE OF JAM3. RX PubMed=20592283; DOI=10.4049/jimmunol.1000556; RA Rabquer B.J., Amin M.A., Teegala N., Shaheen M.K., Tsou P.S., Ruth J.H., RA Lesch C.A., Imhof B.A., Koch A.E.; RT "Junctional adhesion molecule-C is a soluble mediator of angiogenesis."; RL J. Immunol. 185:1777-1785(2010). RN [18] RP FUNCTION (MICROBIAL INFECTION), INTERACTION WITH S.AUREUS HLY, AND RP SUBCELLULAR LOCATION. RX PubMed=20624979; DOI=10.1073/pnas.1001815107; RA Wilke G.A., Bubeck Wardenburg J.; RT "Role of a disintegrin and metalloprotease 10 in Staphylococcus aureus RT alpha-hemolysin-mediated cellular injury."; RL Proc. Natl. Acad. Sci. U.S.A. 107:13473-13478(2010). RN [19] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [20] RP FUNCTION IN CLEAVAGE OF CORIN. RX PubMed=21288900; DOI=10.1074/jbc.m110.185082; RA Jiang J., Wu S., Wang W., Chen S., Peng J., Zhang X., Wu Q.; RT "Ectodomain shedding and autocleavage of the cardiac membrane protease RT corin."; RL J. Biol. Chem. 286:10066-10072(2011). RN [21] RP INTERACTION WITH AP2A1; AP2A2; AP2B1; AP2M1 AND DLG1, SUBCELLULAR LOCATION, RP AND TISSUE SPECIFICITY. RX PubMed=23676497; DOI=10.1172/jci65401; RA Marcello E., Saraceno C., Musardo S., Vara H., de la Fuente A.G., RA Pelucchi S., Di Marino D., Borroni B., Tramontano A., Perez-Otano I., RA Padovani A., Giustetto M., Gardoni F., Di Luca M.; RT "Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's RT disease."; RL J. Clin. Invest. 123:2523-2538(2013). RN [22] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-719, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-719, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [24] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=24990881; DOI=10.1126/scitranslmed.3009093; RA Kleinberger G., Yamanishi Y., Suarez-Calvet M., Czirr E., Lohmann E., RA Cuyvers E., Struyfs H., Pettkus N., Wenninger-Weinzierl A., Mazaheri F., RA Tahirovic S., Lleo A., Alcolea D., Fortea J., Willem M., Lammich S., RA Molinuevo J.L., Sanchez-Valle R., Antonell A., Ramirez A., Heneka M.T., RA Sleegers K., van der Zee J., Martin J.J., Engelborghs S., RA Demirtas-Tatlidede A., Zetterberg H., Van Broeckhoven C., Gurvit H., RA Wyss-Coray T., Hardy J., Colonna M., Haass C.; RT "TREM2 mutations implicated in neurodegeneration impair cell surface RT transport and phagocytosis."; RL Sci. Transl. Med. 6:243RA86-243RA86(2014). RN [25] RP PHOSPHORYLATION AT THR-719. RX PubMed=26091039; DOI=10.1016/j.cell.2015.05.028; RA Tagliabracci V.S., Wiley S.E., Guo X., Kinch L.N., Durrant E., Wen J., RA Xiao J., Cui J., Nguyen K.B., Engel J.L., Coon J.J., Grishin N., RA Pinna L.A., Pagliarini D.J., Dixon J.E.; RT "A single kinase generates the majority of the secreted phosphoproteome."; RL Cell 161:1619-1632(2015). RN [26] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [27] RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND INTERACTION WITH RP TSPAN5; TSPAN14; TSPAN15 AND TSPAN33. RX PubMed=26686862; DOI=10.1007/s00018-015-2111-z; RA Jouannet S., Saint-Pol J., Fernandez L., Nguyen V., Charrin S., RA Boucheix C., Brou C., Milhiet P.E., Rubinstein E.; RT "TspanC8 tetraspanins differentially regulate the cleavage of ADAM10 RT substrates, Notch activation and ADAM10 membrane compartmentalization."; RL Cell. Mol. Life Sci. 73:1895-1915(2016). RN [28] RP FUNCTION. RX PubMed=26876177; DOI=10.1016/j.celrep.2016.01.053; RA Lokau J., Nitz R., Agthe M., Monhasery N., Aparicio-Siegmund S., RA Schumacher N., Wolf J., Moeller-Hackbarth K., Waetzig G.H., Groetzinger J., RA Mueller-Newen G., Rose-John S., Scheller J., Garbers C.; RT "Proteolytic Cleavage Governs Interleukin-11 Trans-signaling."; RL Cell Rep. 14:1761-1773(2016). RN [29] RP INTERACTION WITH TSPAN14, AND DOMAIN. RX PubMed=26668317; DOI=10.1074/jbc.m115.703058; RA Noy P.J., Yang J., Reyat J.S., Matthews A.L., Charlton A.E., Furmston J., RA Rogers D.A., Rainger G.E., Tomlinson M.G.; RT "TspanC8 tetraspanins and A disintegrin and metalloprotease 10 (ADAM10) RT interact via their extracellular regions: evidence for distinct binding RT mechanisms for different TspanC8 proteins."; RL J. Biol. Chem. 291:3145-3157(2016). RN [30] RP FUNCTION (MICROBIAL INFECTION), INTERACTION WITH TSPAN33 AND AFDN, AND RP SUBCELLULAR LOCATION. RX PubMed=30463011; DOI=10.1016/j.celrep.2018.10.088; RA Shah J., Rouaud F., Guerrera D., Vasileva E., Popov L.M., Kelley W.L., RA Rubinstein E., Carette J.E., Amieva M.R., Citi S.; RT "A Dock-and-Lock Mechanism Clusters ADAM10 at Cell-Cell Junctions to RT Promote alpha-Toxin Cytotoxicity."; RL Cell Rep. 25:2132-2147(2018). RN [31] RP CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, ACTIVE SITE, AND MUTAGENESIS OF RP GLU-384. RX PubMed=29430990; DOI=10.1096/fj.201700823rr; RA Brummer T., Pigoni M., Rossello A., Wang H., Noy P.J., Tomlinson M.G., RA Blobel C.P., Lichtenthaler S.F.; RT "The metalloprotease ADAM10 (a disintegrin and metalloprotease 10) RT undergoes rapid, postlysis autocatalytic degradation."; RL FASEB J. 32:3560-3573(2018). RN [32] RP INTERACTION WITH FAM171A1. RX PubMed=30312582; DOI=10.1016/j.ajpath.2018.09.006; RA Rasila T., Saavalainen O., Attalla H., Lankila P., Haglund C., Hoelttae E., RA Andersson L.C.; RT "Astroprincin (FAM171A1, C10orf38): A Regulator of Human Cell Shape and RT Invasive Growth."; RL Am. J. Pathol. 189:177-189(2019). RN [33] RP FUNCTION, AND INTERACTION WITH TSPAN5 AND TSPAN17. RX PubMed=28600292; DOI=10.4049/jimmunol.1600713; RA Reyat J.S., Chimen M., Noy P.J., Szyroka J., Rainger G.E., Tomlinson M.G.; RT "ADAM10-Interacting Tetraspanins Tspan5 and Tspan17 Regulate VE-Cadherin RT Expression and Promote T Lymphocyte Transmigration."; RL J. Immunol. 199:666-676(2017). RN [34] RP FUNCTION, AND INTERACTION WITH TSPAN5 AND TSPAN15. RX PubMed=31792032; DOI=10.26508/lsa.201900444; RA Eschenbrenner E., Jouannet S., Clay D., Chaker J., Boucheix C., Brou C., RA Tomlinson M.G., Charrin S., Rubinstein E.; RT "TspanC8 tetraspanins differentially regulate ADAM10 endocytosis and half- RT life."; RL Life. Sci Alliance 3:0-0(2020). RN [35] RP FUNCTION, AND INTERACTION WITH TSPAN15. RX PubMed=34739841; DOI=10.1016/j.str.2021.10.007; RA Lipper C.H., Gabriel K.H., Seegar T.C.M., Duerr K.L., Tomlinson M.G., RA Blacklow S.C.; RT "Crystal structure of the Tspan15 LEL domain reveals a conserved ADAM10 RT binding site."; RL Structure 30:206-214.e4(2022). RN [36] {ECO:0007744|PDB:6BDZ, ECO:0007744|PDB:6BE6} RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 214-654 IN COMPLEX WITH ZINC, RP CATALYTIC ACTIVITY, FUNCTION, MUTAGENESIS OF GLU-384, GLYCOSYLATION AT RP ASN-278, DISULFIDE BOND, AND ACTIVE SITE. RX PubMed=29224781; DOI=10.1016/j.cell.2017.11.014; RA Seegar T.C.M., Killingsworth L.B., Saha N., Meyer P.A., Patra D., RA Zimmerman B., Janes P.W., Rubinstein E., Nikolov D.B., Skiniotis G., RA Kruse A.C., Blacklow S.C.; RT "Structural basis for regulated proteolysis by the alpha-secretase RT ADAM10."; RL Cell 171:1638-1648.E7(2017). RN [37] {ECO:0007744|PDB:8ESV} RP STRUCTURE BY ELECTRON MICROSCOPY (3.3 ANGSTROMS) OF 214-748 IN COMPLEX WITH RP TSPAN15 AND ZINC, INTERACTION WITH TSPAN15, FUNCTION, BIOPHYSICOCHEMICAL RP PROPERTIES, CATALYTIC ACTIVITY, DISULFIDE BOND, AND MUTAGENESIS OF RP 638-TYR--ARG-646 AND 653-PRO--ARG-656. RX PubMed=37516108; DOI=10.1016/j.cell.2023.06.026; RA Lipper C.H., Egan E.D., Gabriel K.H., Blacklow S.C.; RT "Structural basis for membrane-proximal proteolysis of substrates by RT ADAM10."; RL Cell 186:3632-3641.e10(2023). RN [38] RP VARIANTS AD18 HIS-170 AND GLY-181, AND CHARACTERIZATION OF VARIANTS AD18 RP HIS-170 AND GLY-181. RX PubMed=19608551; DOI=10.1093/hmg/ddp323; RA Kim M., Suh J., Romano D., Truong M.H., Mullin K., Hooli B., Norton D., RA Tesco G., Elliott K., Wagner S.L., Moir R.D., Becker K.D., Tanzi R.E.; RT "Potential late-onset Alzheimer's disease-associated mutations in the RT ADAM10 gene attenuate {alpha}-secretase activity."; RL Hum. Mol. Genet. 18:3987-3996(2009). RN [39] RP VARIANT TYR-176. RX PubMed=21618342; DOI=10.1002/humu.21477; RA Wei X., Moncada-Pazos A., Cal S., Soria-Valles C., Gartner J., Rudloff U., RA Lin J.C., Rosenberg S.A., Lopez-Otin C., Samuels Y.; RT "Analysis of the disintegrin-metalloproteinases family reveals ADAM29 and RT ADAM7 are often mutated in melanoma."; RL Hum. Mutat. 32:E2148-E2175(2011). RN [40] RP VARIANTS RAK SER-139 AND TYR-524. RX PubMed=23666529; DOI=10.1093/hmg/ddt207; RA Kono M., Sugiura K., Suganuma M., Hayashi M., Takama H., Suzuki T., RA Matsunaga K., Tomita Y., Akiyama M.; RT "Whole-exome sequencing identifies ADAM10 mutations as a cause of RT reticulate acropigmentation of Kitamura, a clinical entity distinct from RT Dowling-Degos disease."; RL Hum. Mol. Genet. 22:3524-3533(2013). RN [41] RP CHARACTERIZATION OF VARIANTS AD18 HIS-170 AND GLY-181. RX PubMed=24055016; DOI=10.1016/j.neuron.2013.08.035; RA Suh J., Choi S.H., Romano D.M., Gannon M.A., Lesinski A.N., Kim D.Y., RA Tanzi R.E.; RT "ADAM10 missense mutations potentiate beta-amyloid accumulation by RT impairing prodomain chaperone function."; RL Neuron 80:385-401(2013). CC -!- FUNCTION: Transmembrane metalloprotease which mediates the ectodomain CC shedding of a myriad of transmembrane proteins, including adhesion CC proteins, growth factor precursors and cytokines being essential for CC development and tissue homeostasis (PubMed:11786905, PubMed:12475894, CC PubMed:20592283, PubMed:24990881, PubMed:26686862, PubMed:28600292, CC PubMed:31792032). Associates with six members of the tetraspanin CC superfamily TspanC8 which regulate its exit from the endoplasmic CC reticulum and its substrate selectivity (PubMed:26686862, CC PubMed:28600292, PubMed:31792032, PubMed:34739841, PubMed:37516108). CC Cleaves the membrane-bound precursor of TNF at '76-Ala-|-Val-77' to its CC mature soluble form. Responsible for the proteolytical release of CC soluble JAM3 from endothelial cells surface (PubMed:20592283). CC Responsible for the proteolytic release of several other cell-surface CC proteins, including heparin-binding epidermal growth-like factor, CC ephrin-A2, CD44, CDH2 and for constitutive and regulated alpha- CC secretase cleavage of amyloid precursor protein (APP) (PubMed:11786905, CC PubMed:26686862, PubMed:29224781, PubMed:34739841). Contributes to the CC normal cleavage of the cellular prion protein (PubMed:11477090). CC Involved in the cleavage of the adhesion molecule L1 at the cell CC surface and in released membrane vesicles, suggesting a vesicle-based CC protease activity (PubMed:12475894). Also controls the proteolytic CC processing of Notch and mediates lateral inhibition during neurogenesis CC (By similarity). Required for the development of type 1 transitional B CC cells into marginal zone B cells, probably by cleaving Notch (By CC similarity). Responsible for the FasL ectodomain shedding and for the CC generation of the remnant ADAM10-processed FasL (FasL APL) CC transmembrane form (PubMed:17557115). Also cleaves the ectodomain of CC the integral membrane proteins CORIN and ITM2B (PubMed:19114711, CC PubMed:21288900). Mediates the proteolytic cleavage of LAG3, leading to CC release the secreted form of LAG3 (By similarity). Mediates the CC proteolytic cleavage of IL6R and IL11RA, leading to the release of CC secreted forms of IL6R and IL11RA (PubMed:26876177). Enhances the CC cleavage of CHL1 by BACE1 (By similarity). Cleaves NRCAM (By CC similarity). Cleaves TREM2, resulting in shedding of the TREM2 CC ectodomain (PubMed:24990881). Involved in the development and CC maturation of glomerular and coronary vasculature (By similarity). CC During development of the cochlear organ of Corti, promotes pillar cell CC separation by forming a ternary complex with CADH1 and EPHA4 and CC cleaving CADH1 at adherens junctions (By similarity). May regulate the CC EFNA5-EPHA3 signaling (PubMed:16239146). Regulates leukocyte CC transmigration as a sheddase for the adherens junction protein VE- CC cadherin/CDH5 in endothelial cells (PubMed:28600292). CC {ECO:0000250|UniProtKB:O35598, ECO:0000269|PubMed:11477090, CC ECO:0000269|PubMed:11786905, ECO:0000269|PubMed:12475894, CC ECO:0000269|PubMed:16239146, ECO:0000269|PubMed:17557115, CC ECO:0000269|PubMed:19114711, ECO:0000269|PubMed:20592283, CC ECO:0000269|PubMed:21288900, ECO:0000269|PubMed:24990881, CC ECO:0000269|PubMed:26686862, ECO:0000269|PubMed:26876177, CC ECO:0000269|PubMed:28600292, ECO:0000269|PubMed:29224781, CC ECO:0000269|PubMed:31792032, ECO:0000269|PubMed:34739841, CC ECO:0000269|PubMed:37516108}. CC -!- FUNCTION: (Microbial infection) Promotes the cytotoxic activity of CC S.aureus hly by binding to the toxin at zonula adherens and promoting CC formation of toxin pores. {ECO:0000269|PubMed:20624979, CC ECO:0000269|PubMed:30463011}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Endopeptidase of broad specificity.; EC=3.4.24.81; CC Evidence={ECO:0000269|PubMed:11477090, ECO:0000269|PubMed:11786905, CC ECO:0000269|PubMed:12475894, ECO:0000269|PubMed:16239146, CC ECO:0000269|PubMed:17557115, ECO:0000269|PubMed:19114711, CC ECO:0000269|PubMed:20592283, ECO:0000269|PubMed:21288900, CC ECO:0000269|PubMed:26686862, ECO:0000269|PubMed:29224781, CC ECO:0000269|PubMed:29430990, ECO:0000269|PubMed:37516108, CC ECO:0000305|PubMed:24990881}; CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Evidence={ECO:0000269|PubMed:29224781}; CC Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:29224781}; CC -!- ACTIVITY REGULATION: Catalytically inactive when the propeptide is CC intact and associated with the mature enzyme (By similarity). The CC disintegrin and cysteine-rich regions modulate access of substrates to CC exerts an inhibitory effect on the cleavage of ADAM10 substrates CC (PubMed:29224781). {ECO:0000250|UniProtKB:Q10741, CC ECO:0000269|PubMed:29224781}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=22 uM for substrate (in complex with TSPAN15) CC {ECO:0000269|PubMed:37516108}; CC -!- SUBUNIT: Forms a ternary EFNA5-EPHA3-ADAM10 complex mediating EFNA5 CC extracellular domain shedding by ADAM10 which regulates the EFNA5-EPHA3 CC complex internalization and function, the cleavage occurs in trans, CC with ADAM10 and its substrate being on the membranes of opposing cells CC (PubMed:16239146). Interacts with the clathrin adapter AP2 complex CC subunits AP2A1, AP2A2, AP2B1, and AP2M1; this interaction facilitates CC ADAM10 endocytosis from the plasma membrane during long-term CC potentiation in hippocampal neurons (PubMed:23676497). Forms a ternary CC complex composed of ADAM10, EPHA4 and CADH1; within the complex, ADAM10 CC cleaves CADH1 which disrupts adherens junctions (By similarity). CC Interacts with EPHA2 (By similarity). Interacts with NGF in a divalent CC cation-dependent manner (PubMed:20164177). Interacts with TSPAN14; the CC interaction promotes ADAM10 maturation and cell surface expression CC (PubMed:26668317, PubMed:26686862). Interacts with TSPAN5, TSPAN10, CC TSPAN14, TSPAN15, TSPAN17 and TSPAN33; these interactions regulate CC ADAM10 substrate specificity, endocytosis and turnover CC (PubMed:26668317, PubMed:26686862, PubMed:34739841, PubMed:37516108). CC Interacts (via extracellular domain) with TSPAN33 (via extracellular CC domain) and (via cytoplasmic domain) with AFDN; interaction with CC TSPAN33 allows the docking of ADAM10 to zonula adherens through a CC PDZ11-dependent interaction between TSPAN33 and PLEKHA7 while CC interaction with AFDN locks ADAM10 at zonula adherens CC (PubMed:30463011). Interacts with DLG1; this interaction recruits CC ADAM10 to the cell membrane during long-term depression in hippocampal CC neurons (PubMed:23676497). Interacts (via extracellular domain) with CC BACE1 (via extracellular domain) (By similarity). Interacts with CC FAM171A1 (PubMed:30312582). {ECO:0000250|UniProtKB:O35598, CC ECO:0000269|PubMed:16239146, ECO:0000269|PubMed:20164177, CC ECO:0000269|PubMed:23676497, ECO:0000269|PubMed:26668317, CC ECO:0000269|PubMed:26686862, ECO:0000269|PubMed:30312582, CC ECO:0000269|PubMed:30463011, ECO:0000269|PubMed:34739841, CC ECO:0000269|PubMed:37516108}. CC -!- SUBUNIT: (Microbial infection) Interacts with S.aureus hly; this CC interaction is necessary for toxin pore formation, disruption of focal CC adhesions and S.aureus hly-mediated cytotoxicity. CC {ECO:0000269|PubMed:20624979, ECO:0000269|PubMed:30463011}. CC -!- INTERACTION: CC O14672; P00519: ABL1; NbExp=2; IntAct=EBI-1536151, EBI-375543; CC O14672; P05067: APP; NbExp=7; IntAct=EBI-1536151, EBI-77613; CC O14672; P56817: BACE1; NbExp=3; IntAct=EBI-1536151, EBI-2433139; CC O14672; P60033: CD81; NbExp=9; IntAct=EBI-1536151, EBI-712921; CC O14672; P21926: CD9; NbExp=17; IntAct=EBI-1536151, EBI-4280101; CC O14672; P06241: FYN; NbExp=2; IntAct=EBI-1536151, EBI-515315; CC O14672; Q13588: GRAP; NbExp=2; IntAct=EBI-1536151, EBI-2847510; CC O14672; O75791: GRAP2; NbExp=3; IntAct=EBI-1536151, EBI-740418; CC O14672; P62993: GRB2; NbExp=5; IntAct=EBI-1536151, EBI-401755; CC O14672; P08631: HCK; NbExp=2; IntAct=EBI-1536151, EBI-346340; CC O14672; P06239: LCK; NbExp=3; IntAct=EBI-1536151, EBI-1348; CC O14672; Q9BY11: PACSIN1; NbExp=2; IntAct=EBI-1536151, EBI-721769; CC O14672; Q9UNF0: PACSIN2; NbExp=2; IntAct=EBI-1536151, EBI-742503; CC O14672; Q9UKS6: PACSIN3; NbExp=3; IntAct=EBI-1536151, EBI-77926; CC O14672; Q99961: SH3GL1; NbExp=2; IntAct=EBI-1536151, EBI-697911; CC O14672; Q96RF0: SNX18; NbExp=2; IntAct=EBI-1536151, EBI-298169; CC O14672; P12931: SRC; NbExp=3; IntAct=EBI-1536151, EBI-621482; CC O14672; O95859: TSPAN12; NbExp=2; IntAct=EBI-1536151, EBI-2466403; CC O14672; Q8NG11: TSPAN14; NbExp=9; IntAct=EBI-1536151, EBI-6308913; CC O14672; O95858: TSPAN15; NbExp=12; IntAct=EBI-1536151, EBI-7361096; CC O14672; Q86UF1: TSPAN33; NbExp=3; IntAct=EBI-1536151, EBI-12045841; CC O14672; P62079: TSPAN5; NbExp=12; IntAct=EBI-1536151, EBI-20977525; CC O14672; P07947: YES1; NbExp=2; IntAct=EBI-1536151, EBI-515331; CC PRO_0000029067; P60033: CD81; NbExp=2; IntAct=EBI-21222747, EBI-712921; CC PRO_0000029067; O95859: TSPAN12; NbExp=2; IntAct=EBI-21222747, EBI-2466403; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:20624979, CC ECO:0000269|PubMed:23676497, ECO:0000269|PubMed:24990881, CC ECO:0000269|PubMed:26686862, ECO:0000269|PubMed:29430990, CC ECO:0000269|PubMed:30463011}; Single-pass type I membrane protein CC {ECO:0000305}. Golgi apparatus membrane {ECO:0000269|PubMed:12475894}; CC Single-pass type I membrane protein {ECO:0000305}. Cytoplasmic vesicle, CC clathrin-coated vesicle {ECO:0000269|PubMed:12475894}. Cell projection, CC axon {ECO:0000250|UniProtKB:O35598}. Cell projection, dendrite CC {ECO:0000250|UniProtKB:O35598}. Cell junction, adherens junction CC {ECO:0000269|PubMed:30463011}. Cytoplasm {ECO:0000269|PubMed:30463011}. CC Note=Is localized in the plasma membrane but is also expressed in the CC Golgi apparatus and in clathrin-coated vesicles derived likely from the CC Golgi (PubMed:12475894). During long term depression, it is recruited CC to the cell membrane by DLG1 (PubMed:23676497). The immature form is CC mainly located near cytoplasmic fibrillar structures, while the mature CC form is predominantly located at zonula adherens and the cell membrane CC (PubMed:30463011). The localization and clustering of mature ADAM10 to CC zonula adherens is regulated by AFDN, TSPAN33, PLEKHA7 and PDZD11 CC (PubMed:30463011). {ECO:0000269|PubMed:12475894, CC ECO:0000269|PubMed:23676497, ECO:0000269|PubMed:30463011}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=O14672-1; Sequence=Displayed; CC Name=2; CC IsoId=O14672-2; Sequence=VSP_056401; CC -!- TISSUE SPECIFICITY: Expressed in the brain (at protein level) CC (PubMed:23676497). Expressed in spleen, lymph node, thymus, peripheral CC blood leukocyte, bone marrow, cartilage, chondrocytes and fetal liver CC (PubMed:11511685, PubMed:9016778). {ECO:0000269|PubMed:11511685, CC ECO:0000269|PubMed:23676497, ECO:0000269|PubMed:9016778}. CC -!- INDUCTION: In osteoarthritis affected-cartilage. CC -!- DOMAIN: The propeptide keeps the metalloprotease in a latent form via a CC cysteine switch mechanism. This mechanism may be mediated by a highly CC conserved cysteine (Cys-173) in the propeptide, which interacts and CC neutralizes the zinc-coordinating HEXGHXXGXXHD catalytic core of the CC metalloprotease domain. The dissociation of the cysteine from the zinc CC ion upon the activation-peptide release activates the enzyme. CC {ECO:0000250|UniProtKB:P03956}. CC -!- DOMAIN: The Cys-rich region C-terminal to the disintegrin domain CC functions as a substrate-recognition module, it recognizes the EFNA5- CC EPHA3 complex but not the individual proteins (By similarity). Both CC Cys-rich and stalk region are necessary for interaction with TSPAN5, CC TSPAN10, TSPAN14, TSPAN17, TSPAN33 (PubMed:26668317). Stalk region is CC sufficient for interaction with TSPAN15 (By similarity). CC {ECO:0000250|UniProtKB:O35598, ECO:0000250|UniProtKB:Q10741, CC ECO:0000269|PubMed:26668317}. CC -!- PTM: The precursor is cleaved by furin and PCSK7. CC {ECO:0000250|UniProtKB:Q10741}. CC -!- DISEASE: Reticulate acropigmentation of Kitamura (RAK) [MIM:615537]: A CC rare cutaneous pigmentation disorder characterized by reticulate, CC slightly depressed, sharply demarcated brown macules without CC hypopigmentation, affecting the dorsa of the hands and feet and CC appearing in the first or second decade of life. The macules gradually CC darken and extend to the proximal regions of the extremities. The CC manifestations tend to progress until middle age, after which CC progression of the eruptions stops. The pigmentary augmentation is CC found on the flexor aspects of the wrists, neck, patella and olecranon. CC Other features include breaks in the epidermal ridges on the palms and CC fingers, palmoplantar pits, occasionally plantar keratoderma, and CC partial alopecia. {ECO:0000269|PubMed:23666529}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Alzheimer disease 18 (AD18) [MIM:615590]: A late-onset form of CC Alzheimer disease. Alzheimer disease is a neurodegenerative disorder CC characterized by progressive dementia, loss of cognitive abilities, and CC deposition of fibrillar amyloid proteins as intraneuronal CC neurofibrillary tangles, extracellular amyloid plaques and vascular CC amyloid deposits. The major constituents of these plaques are CC neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that CC are produced by the proteolysis of the transmembrane APP protein. The CC cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, CC such as C31, are also implicated in neuronal death. CC {ECO:0000269|PubMed:19608551, ECO:0000269|PubMed:24055016}. CC Note=Disease susceptibility is associated with variants affecting the CC gene represented in this entry. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/44397/ADAM10"; 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; AF009615; AAC51766.1; -; mRNA. DR EMBL; AK300472; BAG62190.1; -; mRNA. DR EMBL; AC018904; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC091046; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; Z48579; CAA88463.1; -; mRNA. DR CCDS; CCDS10167.1; -. [O14672-1] DR RefSeq; NP_001101.1; NM_001110.4. [O14672-1] DR PDB; 6BDZ; X-ray; 3.10 A; A=220-654. DR PDB; 6BE6; X-ray; 2.80 A; A/B/C/D=214-654. DR PDB; 8ESV; EM; 3.30 A; A=214-748. DR PDBsum; 6BDZ; -. DR PDBsum; 6BE6; -. DR PDBsum; 8ESV; -. DR AlphaFoldDB; O14672; -. DR EMDB; EMD-28580; -. DR SMR; O14672; -. DR BioGRID; 106616; 127. DR DIP; DIP-39889N; -. DR FunCoup; O14672; 3380. DR IntAct; O14672; 163. DR MINT; O14672; -. DR STRING; 9606.ENSP00000260408; -. DR BindingDB; O14672; -. DR ChEMBL; CHEMBL5028; -. DR DrugBank; DB04991; XL784. DR GuidetoPHARMACOLOGY; 1658; -. DR MEROPS; M12.210; -. DR TCDB; 8.A.77.1.4; the sheddase (sheddase) family. DR GlyConnect; 1178; 5 N-Linked glycans (2 sites). DR GlyCosmos; O14672; 5 sites, 6 glycans. DR GlyGen; O14672; 14 sites, 55 N-linked glycans (4 sites), 3 O-linked glycans (8 sites). DR iPTMnet; O14672; -. DR PhosphoSitePlus; O14672; -. DR SwissPalm; O14672; -. DR BioMuta; ADAM10; -. DR jPOST; O14672; -. DR MassIVE; O14672; -. DR PaxDb; 9606-ENSP00000260408; -. DR PeptideAtlas; O14672; -. DR ProteomicsDB; 48162; -. [O14672-1] DR ProteomicsDB; 5144; -. DR Pumba; O14672; -. DR ABCD; O14672; 29 sequenced antibodies. DR Antibodypedia; 3441; 598 antibodies from 44 providers. DR DNASU; 102; -. DR Ensembl; ENST00000260408.8; ENSP00000260408.3; ENSG00000137845.16. [O14672-1] DR GeneID; 102; -. DR KEGG; hsa:102; -. DR MANE-Select; ENST00000260408.8; ENSP00000260408.3; NM_001110.4; NP_001101.1. DR UCSC; uc002afd.3; human. [O14672-1] DR AGR; HGNC:188; -. DR ClinPGx; PA24505; -. DR CTD; 102; -. DR DisGeNET; 102; -. DR GeneCards; ADAM10; -. DR HGNC; HGNC:188; ADAM10. DR HPA; ENSG00000137845; Low tissue specificity. DR MalaCards; ADAM10; -. DR MIM; 602192; gene. DR MIM; 615537; phenotype. DR MIM; 615590; phenotype. DR OpenTargets; ENSG00000137845; -. DR Orphanet; 178307; Reticulate acropigmentation of Kitamura. DR VEuPathDB; HostDB:ENSG00000137845; -. DR eggNOG; KOG3658; Eukaryota. DR GeneTree; ENSGT00940000160579; -. DR HOGENOM; CLU_004602_0_0_1; -. DR InParanoid; O14672; -. DR OMA; MAVFIRC; -. DR OrthoDB; 2149267at2759; -. DR PAN-GO; O14672; 5 GO annotations based on evolutionary models. DR PhylomeDB; O14672; -. DR BioCyc; MetaCyc:ENSG00000137845-MONOMER; -. DR BRENDA; 3.4.24.81; 2681. DR PathwayCommons; O14672; -. DR Reactome; R-HSA-1442490; Collagen degradation. DR Reactome; R-HSA-1474228; Degradation of the extracellular matrix. DR Reactome; R-HSA-177929; Signaling by EGFR. DR Reactome; R-HSA-2122948; Activated NOTCH1 Transmits Signal to the Nucleus. DR Reactome; R-HSA-2644606; Constitutive Signaling by NOTCH1 PEST Domain Mutants. DR Reactome; R-HSA-2660826; Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant. DR Reactome; R-HSA-2691232; Constitutive Signaling by NOTCH1 HD Domain Mutants. DR Reactome; R-HSA-2894862; Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants. DR Reactome; R-HSA-2979096; NOTCH2 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs). DR Reactome; R-HSA-3928665; EPH-ephrin mediated repulsion of cells. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR Reactome; R-HSA-8957275; Post-translational protein phosphorylation. DR Reactome; R-HSA-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-9013700; NOTCH4 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-977225; Amyloid fiber formation. DR SignaLink; O14672; -. DR SIGNOR; O14672; -. DR Agora; ENSG00000137845; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 102; 28 hits in 1161 CRISPR screens. DR ChiTaRS; ADAM10; human. DR GeneWiki; ADAM10; -. DR GenomeRNAi; 102; -. DR Pharos; O14672; Tchem. DR PRO; PR:O14672; -. DR Proteomes; UP000005640; Chromosome 15. DR RNAct; O14672; protein. DR Bgee; ENSG00000137845; Expressed in stromal cell of endometrium and 220 other cell types or tissues. DR ExpressionAtlas; O14672; baseline and differential. DR GO; GO:0005912; C:adherens junction; IEA:UniProtKB-SubCell. DR GO; GO:0030424; C:axon; IEA:UniProtKB-SubCell. DR GO; GO:0009986; C:cell surface; IDA:UniProtKB. DR GO; GO:0030136; C:clathrin-coated vesicle; IEA:UniProtKB-SubCell. DR GO; GO:0030425; C:dendrite; IEA:UniProtKB-SubCell. DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005925; C:focal adhesion; HDA:UniProtKB. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005798; C:Golgi-associated vesicle; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0097038; C:perinuclear endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0046930; C:pore complex; IMP:UniProtKB. DR GO; GO:0014069; C:postsynaptic density; IEA:Ensembl. DR GO; GO:0035579; C:specific granule membrane; TAS:Reactome. DR GO; GO:0097060; C:synaptic membrane; IDA:UniProtKB. DR GO; GO:0070821; C:tertiary granule membrane; TAS:Reactome. DR GO; GO:0097197; C:tetraspanin-enriched microdomain; IDA:UniProtKB. DR GO; GO:0004175; F:endopeptidase activity; IMP:UniProtKB. DR GO; GO:0005178; F:integrin binding; NAS:UniProtKB. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0070573; F:metallodipeptidase activity; IEA:Ensembl. DR GO; GO:0004222; F:metalloendopeptidase activity; IDA:ARUK-UCL. DR GO; GO:1902945; F:metalloendopeptidase activity involved in amyloid precursor protein catabolic process; IMP:UniProtKB. DR GO; GO:0008237; F:metallopeptidase activity; IDA:UniProtKB. DR GO; GO:0042803; F:protein homodimerization activity; IPI:DisProt. DR GO; GO:0017124; F:SH3 domain binding; IEA:UniProtKB-KW. DR GO; GO:0034332; P:adherens junction organization; IEA:Ensembl. DR GO; GO:0042987; P:amyloid precursor protein catabolic process; IMP:UniProtKB. DR GO; GO:0007267; P:cell-cell signaling; NAS:UniProtKB. DR GO; GO:0090102; P:cochlea development; IEA:Ensembl. DR GO; GO:0051089; P:constitutive protein ectodomain proteolysis; IDA:UniProtKB. DR GO; GO:0038004; P:epidermal growth factor receptor ligand maturation; IEA:Ensembl. DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; IEA:Ensembl. DR GO; GO:0022617; P:extracellular matrix disassembly; TAS:Reactome. DR GO; GO:0001701; P:in utero embryonic development; ISS:UniProtKB. DR GO; GO:0007229; P:integrin-mediated signaling pathway; NAS:UniProtKB. DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:UniProtKB. DR GO; GO:0042117; P:monocyte activation; IMP:BHF-UCL. DR GO; GO:0007162; P:negative regulation of cell adhesion; IDA:UniProtKB. DR GO; GO:0010629; P:negative regulation of gene expression; IMP:ARUK-UCL. DR GO; GO:0007219; P:Notch signaling pathway; ISS:UniProtKB. DR GO; GO:0046931; P:pore complex assembly; IMP:UniProtKB. DR GO; GO:0030307; P:positive regulation of cell growth; IMP:BHF-UCL. DR GO; GO:0030335; P:positive regulation of cell migration; IMP:BHF-UCL. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:BHF-UCL. DR GO; GO:0010820; P:positive regulation of T cell chemotaxis; IMP:BHF-UCL. DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IDA:ARUK-UCL. DR GO; GO:1903265; P:positive regulation of tumor necrosis factor-mediated signaling pathway; IDA:ARUK-UCL. DR GO; GO:0099173; P:postsynapse organization; IEA:Ensembl. DR GO; GO:0140249; P:protein catabolic process at postsynapse; IEA:Ensembl. DR GO; GO:0016485; P:protein processing; ISS:ARUK-UCL. DR GO; GO:0098696; P:regulation of neurotransmitter receptor localization to postsynaptic specialization membrane; IEA:Ensembl. DR GO; GO:0008593; P:regulation of Notch signaling pathway; IEA:Ensembl. DR GO; GO:0099175; P:regulation of postsynapse organization; IEA:Ensembl. DR GO; GO:1901342; P:regulation of vasculature development; IEA:Ensembl. DR GO; GO:0034612; P:response to tumor necrosis factor; IDA:BHF-UCL. DR CDD; cd04270; ZnMc_TACE_like; 1. DR DisProt; DP02318; -. DR FunFam; 3.40.390.10:FF:000011; Disintegrin and metalloproteinase domain-containing protein 10; 1. DR FunFam; 4.10.70.10:FF:000002; disintegrin and metalloproteinase domain-containing protein 10; 1. DR Gene3D; 3.40.390.10; Collagenase (Catalytic Domain); 1. DR Gene3D; 4.10.70.10; Disintegrin domain; 1. DR InterPro; IPR034025; ADAM10_ADAM17. DR InterPro; IPR049038; ADAM10_Cys-rich. DR InterPro; IPR051489; ADAM_Metalloproteinase. DR InterPro; IPR001762; Disintegrin_dom. DR InterPro; IPR036436; Disintegrin_dom_sf. DR InterPro; IPR024079; MetalloPept_cat_dom_sf. DR InterPro; IPR001590; Peptidase_M12B. DR PANTHER; PTHR45702; ADAM10/ADAM17 METALLOPEPTIDASE FAMILY MEMBER; 1. DR PANTHER; PTHR45702:SF4; DISINTEGRIN AND METALLOPROTEINASE DOMAIN-CONTAINING PROTEIN 10; 1. DR Pfam; PF21299; ADAM10_Cys-rich; 1. DR Pfam; PF00200; Disintegrin; 1. DR Pfam; PF13574; Reprolysin_2; 1. DR SMART; SM00050; DISIN; 1. DR SUPFAM; SSF57552; Blood coagulation inhibitor (disintegrin); 1. DR SUPFAM; SSF55486; Metalloproteases ('zincins'), catalytic domain; 1. DR PROSITE; PS50215; ADAM_MEPRO; 1. DR PROSITE; PS50214; DISINTEGRIN_2; 1. DR PROSITE; PS00142; ZINC_PROTEASE; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Alzheimer disease; Amyloidosis; KW Cell junction; Cell membrane; Cell projection; KW Cleavage on pair of basic residues; Cytoplasm; Cytoplasmic vesicle; KW Direct protein sequencing; Disease variant; Disulfide bond; Glycoprotein; KW Golgi apparatus; Hydrolase; Membrane; Metal-binding; Metalloprotease; KW Neurodegeneration; Notch signaling pathway; Phosphoprotein; Protease; KW Proteomics identification; Reference proteome; SH3-binding; Signal; KW Transmembrane; Transmembrane helix; Zinc; Zymogen. FT SIGNAL 1..19 FT /evidence="ECO:0000255" FT PROPEP 20..213 FT /evidence="ECO:0000250|UniProtKB:Q10741" FT /id="PRO_0000029066" FT CHAIN 214..748 FT /note="Disintegrin and metalloproteinase domain-containing FT protein 10" FT /id="PRO_0000029067" FT TOPO_DOM 20..672 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 673..693 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 694..748 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 220..456 FT /note="Peptidase M12B" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00276" FT DOMAIN 457..551 FT /note="Disintegrin" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00068" FT REGION 704..748 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 734..748 FT /note="Interaction with AP2A1, AP2A2 and AP2M1" FT /evidence="ECO:0000250|UniProtKB:O35598" FT MOTIF 171..178 FT /note="Cysteine switch" FT /evidence="ECO:0000250" FT MOTIF 708..715 FT /note="SH3-binding" FT /evidence="ECO:0000255" FT MOTIF 722..728 FT /note="SH3-binding" FT /evidence="ECO:0000255" FT ACT_SITE 384 FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0000269|PubMed:29430990" FT BINDING 173 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT /note="in inhibited form" FT /evidence="ECO:0000250|UniProtKB:P03956" FT BINDING 383 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:24055016, FT ECO:0000269|PubMed:29224781, ECO:0000269|PubMed:37516108, FT ECO:0007744|PDB:6BDZ, ECO:0007744|PDB:6BE6, FT ECO:0007744|PDB:8ESV" FT BINDING 387 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0000269|PubMed:37516108, ECO:0007744|PDB:6BE6, FT ECO:0007744|PDB:8ESV" FT BINDING 393 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:24055016, FT ECO:0000269|PubMed:29224781, ECO:0000269|PubMed:37516108, FT ECO:0007744|PDB:6BDZ, ECO:0007744|PDB:6BE6, FT ECO:0007744|PDB:8ESV" FT SITE 213..214 FT /note="Cleavage; by furin and PCSK7" FT /evidence="ECO:0000250|UniProtKB:Q10741" FT MOD_RES 719 FT /note="Phosphothreonine; by FAM20C" FT /evidence="ECO:0000269|PubMed:26091039, FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569" FT CARBOHYD 267 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 278 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16263699, FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:19349973, FT ECO:0000269|PubMed:29224781, ECO:0007744|PDB:6BDZ, FT ECO:0007744|PDB:6BE6" FT CARBOHYD 439 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 551 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 222..313 FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0000269|PubMed:37516108, ECO:0007744|PDB:6BDZ, FT ECO:0007744|PDB:6BE6, ECO:0007744|PDB:8ESV" FT DISULFID 344..451 FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0000269|PubMed:37516108, ECO:0007744|PDB:6BDZ, FT ECO:0007744|PDB:6BE6, ECO:0007744|PDB:8ESV" FT DISULFID 399..435 FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0000269|PubMed:37516108, ECO:0007744|PDB:6BDZ, FT ECO:0007744|PDB:6BE6, ECO:0007744|PDB:8ESV" FT DISULFID 460..495 FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0000269|PubMed:37516108, ECO:0007744|PDB:6BDZ, FT ECO:0007744|PDB:6BE6, ECO:0007744|PDB:8ESV" FT DISULFID 471..484 FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0000269|PubMed:37516108, ECO:0007744|PDB:6BDZ, FT ECO:0007744|PDB:6BE6, ECO:0007744|PDB:8ESV" FT DISULFID 473..479 FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0000269|PubMed:37516108, ECO:0007744|PDB:6BDZ, FT ECO:0007744|PDB:6BE6, ECO:0007744|PDB:8ESV" FT DISULFID 483..515 FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0000269|PubMed:37516108, ECO:0007744|PDB:6BDZ, FT ECO:0007744|PDB:6BE6, ECO:0007744|PDB:8ESV" FT DISULFID 503..511 FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0000269|PubMed:37516108, ECO:0007744|PDB:6BDZ, FT ECO:0007744|PDB:6BE6, ECO:0007744|PDB:8ESV" FT DISULFID 510..536 FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0000269|PubMed:37516108, ECO:0007744|PDB:6BDZ, FT ECO:0007744|PDB:6BE6, ECO:0007744|PDB:8ESV" FT DISULFID 524..543 FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0000269|PubMed:37516108, ECO:0007744|PDB:6BDZ, FT ECO:0007744|PDB:6BE6, ECO:0007744|PDB:8ESV" FT DISULFID 530..562 FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0000269|PubMed:37516108, ECO:0007744|PDB:6BDZ, FT ECO:0007744|PDB:6BE6, ECO:0007744|PDB:8ESV" FT DISULFID 555..567 FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0000269|PubMed:37516108, ECO:0007744|PDB:6BDZ, FT ECO:0007744|PDB:6BE6, ECO:0007744|PDB:8ESV" FT DISULFID 572..598 FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0000269|PubMed:37516108, ECO:0007744|PDB:6BDZ, FT ECO:0007744|PDB:6BE6, ECO:0007744|PDB:8ESV" FT DISULFID 580..607 FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0000269|PubMed:37516108, ECO:0007744|PDB:6BDZ, FT ECO:0007744|PDB:6BE6, ECO:0007744|PDB:8ESV" FT DISULFID 582..597 FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0000269|PubMed:37516108, ECO:0007744|PDB:6BDZ, FT ECO:0007744|PDB:6BE6, ECO:0007744|PDB:8ESV" FT DISULFID 594..639 FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0000269|PubMed:37516108, ECO:0007744|PDB:6BDZ, FT ECO:0007744|PDB:6BE6, ECO:0007744|PDB:8ESV" FT DISULFID 632..645 FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0007744|PDB:6BDZ, ECO:0007744|PDB:6BE6" FT VAR_SEQ 19..319 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_056401" FT VARIANT 139 FT /note="P -> S (in RAK; dbSNP:rs483352912)" FT /evidence="ECO:0000269|PubMed:23666529" FT /id="VAR_070907" FT VARIANT 170 FT /note="Q -> H (in AD18; associated with disease FT susceptibility; significantly attenuates alpha-secretase FT activity of the enzyme; shifts APP processing toward beta- FT secretase-mediated cleavage resulting in enhanced amyloid- FT beta plaque load and reactive gliosis; dbSNP:rs61751103)" FT /evidence="ECO:0000269|PubMed:19608551, FT ECO:0000269|PubMed:24055016" FT /id="VAR_070908" FT VARIANT 176 FT /note="H -> Y (in a cutaneous metastatic melanoma sample; FT somatic mutation; dbSNP:rs267604273)" FT /evidence="ECO:0000269|PubMed:21618342" FT /id="VAR_066309" FT VARIANT 181 FT /note="R -> G (in AD18; associated with disease FT susceptibility; significantly attenuates alpha-secretase FT activity of the enzyme; shifts APP processing toward beta- FT secretase-mediated cleavage resulting in enhanced amyloid- FT beta plaque load and reactive gliosis; dbSNP:rs145518263)" FT /evidence="ECO:0000269|PubMed:19608551, FT ECO:0000269|PubMed:24055016" FT /id="VAR_070909" FT VARIANT 524 FT /note="C -> Y (in RAK; dbSNP:rs483352916)" FT /evidence="ECO:0000269|PubMed:23666529" FT /id="VAR_070910" FT MUTAGEN 384 FT /note="E->A: Loss of proteolytic activity. Abrogates APP FT cleavage. Reduces Notch signaling." FT /evidence="ECO:0000269|PubMed:29224781, FT ECO:0000269|PubMed:29430990" FT MUTAGEN 638..646 FT /note="YCDVFMRCR->ACDVFMRCA: Strongly reduces interaction FT and ADAM10 maturation." FT /evidence="ECO:0000269|PubMed:37516108" FT MUTAGEN 638..646 FT /note="YCDVFMRCR->ECDVFMRCE: Strongly reduces interaction FT and prevents ADAM10 maturation." FT /evidence="ECO:0000269|PubMed:37516108" FT MUTAGEN 653..656 FT /note="PLAR->AAAA: Strongly reduces interaction and FT prevents ADAM10 maturation." FT /evidence="ECO:0000269|PubMed:37516108" FT CONFLICT 162 FT /note="N -> SERLKLRLRKLMSLELWTSCCLPCALLLHSWKKAVNSHCLYFKDFWG FT FSEIY (in Ref. 2; CAA88463)" FT /evidence="ECO:0000305" FT CONFLICT 212 FT /note="K -> R (in Ref. 2; CAA88463)" FT /evidence="ECO:0000305" FT CONFLICT 296 FT /note="G -> S (in Ref. 2; CAA88463)" FT /evidence="ECO:0000305" FT STRAND 219..228 FT /evidence="ECO:0007829|PDB:6BE6" FT HELIX 230..236 FT /evidence="ECO:0007829|PDB:6BE6" FT HELIX 239..258 FT /evidence="ECO:0007829|PDB:6BE6" FT STRAND 269..277 FT /evidence="ECO:0007829|PDB:6BE6" FT HELIX 280..284 FT /evidence="ECO:0007829|PDB:6BE6" FT HELIX 289..291 FT /evidence="ECO:0007829|PDB:8ESV" FT HELIX 297..305 FT /evidence="ECO:0007829|PDB:6BE6" FT STRAND 313..322 FT /evidence="ECO:0007829|PDB:6BE6" FT HELIX 324..326 FT /evidence="ECO:0007829|PDB:6BE6" FT STRAND 329..331 FT /evidence="ECO:0007829|PDB:6BE6" FT STRAND 336..338 FT /evidence="ECO:0007829|PDB:6BE6" FT STRAND 348..350 FT /evidence="ECO:0007829|PDB:6BE6" FT STRAND 359..367 FT /evidence="ECO:0007829|PDB:6BE6" FT HELIX 374..388 FT /evidence="ECO:0007829|PDB:6BE6" FT TURN 397..399 FT /evidence="ECO:0007829|PDB:6BE6" FT HELIX 401..403 FT /evidence="ECO:0007829|PDB:6BE6" FT HELIX 407..411 FT /evidence="ECO:0007829|PDB:6BE6" FT HELIX 428..430 FT /evidence="ECO:0007829|PDB:6BE6" FT HELIX 434..447 FT /evidence="ECO:0007829|PDB:6BE6" FT HELIX 448..450 FT /evidence="ECO:0007829|PDB:6BE6" FT STRAND 462..464 FT /evidence="ECO:0007829|PDB:6BE6" FT TURN 476..478 FT /evidence="ECO:0007829|PDB:6BE6" FT STRAND 482..484 FT /evidence="ECO:0007829|PDB:8ESV" FT TURN 491..495 FT /evidence="ECO:0007829|PDB:6BE6" FT TURN 505..507 FT /evidence="ECO:0007829|PDB:6BE6" FT STRAND 509..511 FT /evidence="ECO:0007829|PDB:6BE6" FT STRAND 515..517 FT /evidence="ECO:0007829|PDB:8ESV" FT STRAND 523..525 FT /evidence="ECO:0007829|PDB:6BE6" FT STRAND 529..531 FT /evidence="ECO:0007829|PDB:6BE6" FT STRAND 553..555 FT /evidence="ECO:0007829|PDB:6BDZ" FT TURN 556..559 FT /evidence="ECO:0007829|PDB:6BE6" FT STRAND 560..563 FT /evidence="ECO:0007829|PDB:6BE6" FT STRAND 566..569 FT /evidence="ECO:0007829|PDB:6BE6" FT HELIX 571..575 FT /evidence="ECO:0007829|PDB:6BE6" FT STRAND 577..580 FT /evidence="ECO:0007829|PDB:6BE6" FT HELIX 591..593 FT /evidence="ECO:0007829|PDB:8ESV" FT STRAND 597..600 FT /evidence="ECO:0007829|PDB:6BE6" FT HELIX 604..606 FT /evidence="ECO:0007829|PDB:6BE6" FT HELIX 614..617 FT /evidence="ECO:0007829|PDB:6BE6" FT STRAND 630..632 FT /evidence="ECO:0007829|PDB:6BDZ" FT TURN 633..636 FT /evidence="ECO:0007829|PDB:6BE6" FT STRAND 637..639 FT /evidence="ECO:0007829|PDB:6BE6" FT STRAND 645..647 FT /evidence="ECO:0007829|PDB:6BE6" FT HELIX 653..662 FT /evidence="ECO:0007829|PDB:8ESV" FT HELIX 665..669 FT /evidence="ECO:0007829|PDB:8ESV" SQ SEQUENCE 748 AA; 84142 MW; 0881E65B17022A71 CRC64; MVLLRVLILL LSWAAGMGGQ YGNPLNKYIR HYEGLSYNVD SLHQKHQRAK RAVSHEDQFL RLDFHAHGRH FNLRMKRDTS LFSDEFKVET SNKVLDYDTS HIYTGHIYGE EGSFSHGSVI DGRFEGFIQT RGGTFYVEPA ERYIKDRTLP FHSVIYHEDD INYPHKYGPQ GGCADHSVFE RMRKYQMTGV EEVTQIPQEE HAANGPELLR KKRTTSAEKN TCQLYIQTDH LFFKYYGTRE AVIAQISSHV KAIDTIYQTT DFSGIRNISF MVKRIRINTT ADEKDPTNPF RFPNIGVEKF LELNSEQNHD DYCLAYVFTD RDFDDGVLGL AWVGAPSGSS GGICEKSKLY SDGKKKSLNT GIITVQNYGS HVPPKVSHIT FAHEVGHNFG SPHDSGTECT PGESKNLGQK ENGNYIMYAR ATSGDKLNNN KFSLCSIRNI SQVLEKKRNN CFVESGQPIC GNGMVEQGEE CDCGYSDQCK DECCFDANQP EGRKCKLKPG KQCSPSQGPC CTAQCAFKSK SEKCRDDSDC AREGICNGFT ALCPASDPKP NFTDCNRHTQ VCINGQCAGS ICEKYGLEEC TCASSDGKDD KELCHVCCMK KMDPSTCAST GSVQWSRHFS GRTITLQPGS PCNDFRGYCD VFMRCRLVDA DGPLARLKKA IFSPELYENI AEWIVAHWWA VLLMGIALIM LMAGFIKICS VHTPSSNPKL PPPKPLPGTL KRRRPPQPIQ QPQRQRPRES YQMGHMRR // ID APOE_HUMAN Reviewed; 317 AA. AC P02649; B2RC15; C0JYY5; Q9P2S4; DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot. DT 21-JUL-1986, sequence version 1. DT 28-JAN-2026, entry version 278. DE RecName: Full=Apolipoprotein E {ECO:0000305}; DE Short=Apo-E; DE Flags: Precursor; GN Name=APOE {ECO:0000312|HGNC:HGNC:613}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ALLELE APOE*3). RX PubMed=6325438; DOI=10.1016/s0021-9258(18)91039-2; RA Zannis V.I., McPherson J., Goldberger G., Karathanasis S.K., Breslow J.L.; RT "Synthesis, intracellular processing, and signal peptide of human RT apolipoprotein E."; RL J. Biol. Chem. 259:5495-5499(1984). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS THR-117 AND PRO-170. RX PubMed=6327682; DOI=10.1016/s0021-9258(20)82169-3; RA McLean J.W., Elshourbagy N.A., Chang D.J., Mahley R.W., Taylor J.M.; RT "Human apolipoprotein E mRNA. cDNA cloning and nucleotide sequencing of a RT new variant."; RL J. Biol. Chem. 259:6498-6504(1984). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALLELE APOE*4), AND VARIANT AD2 ARG-130. RX PubMed=2987927; DOI=10.1073/pnas.82.10.3445; RA Paik Y.-K., Chang D.J., Reardon C.A., Davies G.E., Mahley R.W., RA Taylor J.M.; RT "Nucleotide sequence and structure of the human apolipoprotein E gene."; RL Proc. Natl. Acad. Sci. U.S.A. 82:3445-3449(1985). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALLELE APOE*2), AND VARIANT CYS-176. RX PubMed=3243553; DOI=10.1016/0888-7543(88)90130-9; RA Emi M., Wu L.L., Robertson M.A., Myers R.L., Hegele R.A., Williams R.R., RA White R., Lalouel J.-M.; RT "Genotyping and sequence analysis of apolipoprotein E isoforms."; RL Genomics 3:373-379(1988). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALLELE APOE*3). RX PubMed=10520737; DOI=10.3109/10425179809086433; RA Freitas E.M., Zhang W.J., Lalonde J.P., Tay G.K., Gaudieri S., RA Ashworth L.K., Van Bockxmeer F.M., Dawkins R.L.; RT "Sequencing of 42kb of the APO E-C2 gene cluster reveals a new gene: RT PEREC1."; RL DNA Seq. 9:89-100(1998). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALLELE APOE*3), AND VARIANTS PRO-46; RP ARG-130; CYS-163 AND CYS-176. RX PubMed=11042151; DOI=10.1101/gr.146900; RA Nickerson D.A., Taylor S.L., Fullerton S.M., Weiss K.M., Clark A.G., RA Stengard J.H., Salomaa V., Boerwinkle E., Sing C.F.; RT "Sequence diversity and large-scale typing of SNPs in the human RT apolipoprotein E gene."; RL Genome Res. 10:1532-1545(2000). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ALLELE APOE*3). RC TISSUE=Cerebellum; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALLELE APOE*3). RG NHLBI resequencing and genotyping service (RS&G); RL Submitted (DEC-2008) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ALLELE APOE*3). RC TISSUE=Eye; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 16-78, AND VARIANT HIS-64. RC TISSUE=Blood; RA Imura T., Kimura H., Kawasaki M.; RT "A new apolipoprotein E variant (Gln46-->His)."; RL Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases. RN [11] RP NUCLEOTIDE SEQUENCE [MRNA] OF 99-317 (ALLELE APOE*3). RX PubMed=6897404; DOI=10.1016/s0021-9258(18)33328-3; RA Breslow J.L., McPherson J., Nussbaum A.L., Williams H.W., Lofquist-Kahl F., RA Karathanasis S.K., Zannis V.I.; RT "Identification and DNA sequence of a human apolipoprotein E cDNA clone."; RL J. Biol. Chem. 257:14639-14641(1982). RN [12] RP ERRATUM OF PUBMED:6897404. RA Breslow J.L., McPherson J., Nussbaum A.L., Williams H.W., Lofquist-Kahl F., RA Karathanasis S.K., Zannis V.I.; RL J. Biol. Chem. 258:11422-11422(1983). RN [13] RP PROTEIN SEQUENCE OF 19-317 (ALLELE APOE*2). RX PubMed=7068630; DOI=10.1016/s0021-9258(18)34702-1; RA Rall S.C. Jr., Weisgraber K.H., Mahley R.W.; RT "Human apolipoprotein E. The complete amino acid sequence."; RL J. Biol. Chem. 257:4171-4178(1982). RN [14] RP FUNCTION IN LIPOPROTEINS CONVERSION. RX PubMed=6860692; DOI=10.1016/0005-2760(83)90047-4; RA Marcel Y.L., Vezina C., Milne R.W.; RT "Cholesteryl ester and apolipoprotein E transfer between human high density RT lipoproteins and chylomicrons."; RL Biochim. Biophys. Acta 750:411-417(1983). RN [15] RP HEPARIN-BINDING SITES. RX PubMed=3947350; DOI=10.1016/s0006-291x(86)80489-2; RA Cardin A.D., Hirose N., Blankenship D.T., Jackson R.L., Harmony J.A.K., RA Sparrow D.A., Sparrow J.T.; RT "Binding of a high reactive heparin to human apolipoprotein E: RT identification of two heparin-binding domains."; RL Biochem. Biophys. Res. Commun. 134:783-789(1986). RN [16] RP TISSUE SPECIFICITY. RX PubMed=3115992; DOI=10.1016/s0021-9258(18)47945-8; RA Pitas R.E., Boyles J.K., Lee S.H., Hui D., Weisgraber K.H.; RT "Lipoproteins and their receptors in the central nervous system. RT Characterization of the lipoproteins in cerebrospinal fluid and RT identification of apolipoprotein B,E(LDL) receptors in the brain."; RL J. Biol. Chem. 262:14352-14360(1987). RN [17] RP INTERACTION WITH SORL1. RX PubMed=30448281; DOI=10.1016/j.cca.2018.11.024; RA Yano K., Hirayama S., Misawa N., Furuta A., Ueno T., Motoi Y., Seino U., RA Ebinuma H., Ikeuchi T., Schneider W.J., Bujo H., Miida T.; RT "Soluble LR11 competes with amyloid beta in binding to cerebrospinal fluid- RT high-density lipoprotein."; RL Clin. Chim. Acta 489:29-34(2019). RN [18] RP CHARACTERIZATION OF VARIANTS SER-154 AND PRO-170, AND MUTAGENESIS OF RP SER-157; HIS-158; LYS-161; LEU-162; LEU-167 AND ARG-168. RX PubMed=2831187; DOI=10.1016/s0021-9258(18)68957-4; RA Lalazar A., Weisgraber K.H., Rall S.C. Jr., Giladi H., Innerarity T.L., RA Levanon A.Z., Boyles J.K., Amit B., Gorecki M., Mahley R.W.; RT "Site-specific mutagenesis of human apolipoprotein E. Receptor binding RT activity of variants with single amino acid substitutions."; RL J. Biol. Chem. 263:3542-3545(1988). RN [19] RP SUBCELLULAR LOCATION, GLYCOSYLATION AT THR-212, AND MUTAGENESIS OF THR-212. RX PubMed=2498325; DOI=10.1016/s0021-9258(18)81907-x; RA Wernette-Hammond M.E., Lauer S.J., Corsini A., Walker D., Taylor J.M., RA Rall S.C. Jr.; RT "Glycosylation of human apolipoprotein E. The carbohydrate attachment site RT is threonine 194."; RL J. Biol. Chem. 264:9094-9101(1989). RN [20] RP FUNCTION IN VLDL CLEARANCE. RX PubMed=2762297; DOI=10.1073/pnas.86.15.5810; RA Kowal R.C., Herz J., Goldstein J.L., Esser V., Brown M.S.; RT "Low density lipoprotein receptor-related protein mediates uptake of RT cholesteryl esters derived from apoprotein E-enriched lipoproteins."; RL Proc. Natl. Acad. Sci. U.S.A. 86:5810-5814(1989). RN [21] RP REGION, AND CHARACTERIZATION OF VARIANT ARG-130 AND ARG-176. RX PubMed=2280190; RA Weisgraber K.H.; RT "Apolipoprotein E distribution among human plasma lipoproteins: role of the RT cysteine-arginine interchange at residue 112."; RL J. Lipid Res. 31:1503-1511(1990). RN [22] RP FUNCTION IN CHYLOMICRONS CLEARANCE, AND SUBCELLULAR LOCATION. RX PubMed=1911868; DOI=10.1016/0005-2760(91)90138-8; RA Arnon R., Sehayek E., Vogel T., Eisenberg S.; RT "Effects of exogenous apo E-3 and of cholesterol-enriched meals on the RT cellular metabolism of human chylomicrons and their remnants."; RL Biochim. Biophys. Acta 1085:336-342(1991). RN [23] RP FUNCTION IN VLDL AND IDL CLEARANCE. RX PubMed=1917954; DOI=10.1016/s0021-9258(18)55263-7; RA Sehayek E., Eisenberg S.; RT "Mechanisms of inhibition by apolipoprotein C of apolipoprotein E-dependent RT cellular metabolism of human triglyceride-rich lipoproteins through the low RT density lipoprotein receptor pathway."; RL J. Biol. Chem. 266:18259-18267(1991). RN [24] RP SUBUNIT, SUBCELLULAR LOCATION, AND REGION. RX PubMed=8340399; DOI=10.1016/s0021-9258(18)82318-3; RA Westerlund J.A., Weisgraber K.H.; RT "Discrete carboxyl-terminal segments of apolipoprotein E mediate RT lipoprotein association and protein oligomerization."; RL J. Biol. Chem. 268:15745-15750(1993). RN [25] RP INTERACTION WITH APP/A4 AMYLOID-BETA PEPTIDE, AND CHARACTERIZATION OF RP VARIANT AD2 ARG-130. RX PubMed=8367470; DOI=10.1073/pnas.90.17.8098; RA Strittmatter W.J., Weisgraber K.H., Huang D.Y., Dong L.M., Salvesen G.S., RA Pericak-Vance M., Schmechel D., Saunders A.M., Goldgaber D., Roses A.D.; RT "Binding of human apolipoprotein E to synthetic amyloid beta peptide: RT isoform-specific effects and implications for late-onset Alzheimer RT disease."; RL Proc. Natl. Acad. Sci. U.S.A. 90:8098-8102(1993). RN [26] RP INTERACTION WITH MAP2, AND CHARACTERIZATION OF VARIANT AD2 ARG-130. RX PubMed=7891887; DOI=10.1016/0304-3940(94)90204-6; RA Huang D.Y., Goedert M., Jakes R., Weisgraber K.H., Garner C.C., RA Saunders A.M., Pericak-Vance M.A., Schmechel D.E., Roses A.D., RA Strittmatter W.J.; RT "Isoform-specific interactions of apolipoprotein E with the microtubule- RT associated protein MAP2c: implications for Alzheimer's disease."; RL Neurosci. Lett. 182:55-58(1994). RN [27] RP INTERACTION WITH MAPT, AND CHARACTERIZATION OF VARIANT AD2 ARG-130. RX PubMed=7972031; DOI=10.1073/pnas.91.23.11183; RA Strittmatter W.J., Saunders A.M., Goedert M., Weisgraber K.H., Dong L.M., RA Jakes R., Huang D.Y., Pericak-Vance M., Schmechel D., Roses A.D.; RT "Isoform-specific interactions of apolipoprotein E with microtubule- RT associated protein tau: implications for Alzheimer disease."; RL Proc. Natl. Acad. Sci. U.S.A. 91:11183-11186(1994). RN [28] RP FUNCTION, AND LRP2-BINDING. RX PubMed=7768901; DOI=10.1074/jbc.270.22.13070; RA Kounnas M.Z., Loukinova E.B., Stefansson S., Harmony J.A.K., Brewer B.H., RA Strickland D.K., Argraves W.S.; RT "Identification of glycoprotein 330 as an endocytic receptor for RT apolipoprotein J/clusterin."; RL J. Biol. Chem. 270:13070-13075(1995). RN [29] RP FUNCTION IN NEURITE OUTGROWTH, LRP-BINDING, AND CHARACTERIZATION OF VARIANT RP AD2 ARG-130. RX PubMed=8939961; DOI=10.1074/jbc.271.47.30121; RA Fagan A.M., Bu G., Sun Y., Daugherty A., Holtzman D.M.; RT "Apolipoprotein E-containing high density lipoprotein promotes neurite RT outgrowth and is a ligand for the low density lipoprotein receptor-related RT protein."; RL J. Biol. Chem. 271:30121-30125(1996). RN [30] RP FUNCTION IN HDL CLEARANCE, AND HEPARAN SULFATE-BINDING. RX PubMed=9395455; DOI=10.1074/jbc.272.50.31285; RA Ji Z.S., Dichek H.L., Miranda R.D., Mahley R.W.; RT "Heparan sulfate proteoglycans participate in hepatic lipase and RT apolipoprotein E-mediated binding and uptake of plasma lipoproteins, RT including high density lipoproteins."; RL J. Biol. Chem. 272:31285-31292(1997). RN [31] RP FUNCTION, HEPARAN-SULFATE-BINDING, AND SUBCELLULAR LOCATION. RX PubMed=9488694; DOI=10.1074/jbc.273.10.5645; RA Burgess J.W., Gould D.R., Marcel Y.L.; RT "The HepG2 extracellular matrix contains separate heparinase- and lipid- RT releasable pools of ApoE. Implications for hepatic lipoprotein RT metabolism."; RL J. Biol. Chem. 273:5645-5654(1998). RN [32] RP TISSUE SPECIFICITY. RX PubMed=10027417; DOI=10.1016/s0002-9440(10)65305-9; RA Xu P.T., Gilbert J.R., Qiu H.L., Ervin J., Rothrock-Christian T.R., RA Hulette C., Schmechel D.E.; RT "Specific regional transcription of apolipoprotein E in human brain RT neurons."; RL Am. J. Pathol. 154:601-611(1999). RN [33] RP GLYCATION AT LYS-93, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=10452964; DOI=10.1016/s0925-4439(99)00047-2; RA Shuvaev V.V., Fujii J., Kawasaki Y., Itoh H., Hamaoka R., Barbier A., RA Ziegler O., Siest G., Taniguchi N.; RT "Glycation of apolipoprotein E impairs its binding to heparin: RT identification of the major glycation site."; RL Biochim. Biophys. Acta 1454:296-308(1999). RN [34] RP PTM, AND CHARACTERIZATION OF VARIANT AD2 ARG-130. RX PubMed=11447277; DOI=10.1073/pnas.151254698; RA Huang Y., Liu X.Q., Wyss-Coray T., Brecht W.J., Sanan D.A., Mahley R.W.; RT "Apolipoprotein E fragments present in Alzheimer's disease brains induce RT neurofibrillary tangle-like intracellular inclusions in neurons."; RL Proc. Natl. Acad. Sci. U.S.A. 98:8838-8843(2001). RN [35] RP FUNCTION, LRP8-BINDING, AND CHARACTERIZATION OF VARIANT CYS-176. RX PubMed=12950167; DOI=10.1021/bi027093c; RA Li X., Kypreos K., Zanni E.E., Zannis V.; RT "Domains of apoE required for binding to apoE receptor 2 and to RT phospholipids: implications for the functions of apoE in the brain."; RL Biochemistry 42:10406-10417(2003). RN [36] RP FUNCTION IN REVERSE CHOLESTEROL TRANSPORT, AND INTERACTION WITH ABCA1. RX PubMed=14754908; DOI=10.1194/jlr.m300418-jlr200; RA Krimbou L., Denis M., Haidar B., Carrier M., Marcil M., Genest J. Jr.; RT "Molecular interactions between apoE and ABCA1: impact on apoE RT lipidation."; RL J. Lipid Res. 45:839-848(2004). RN [37] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT THR-212; THR-307 AND SER-308, AND RP STRUCTURE OF CARBOHYDRATES. RC TISSUE=Cerebrospinal fluid; RX PubMed=19838169; DOI=10.1038/nmeth.1392; RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E., Brinkmalm G., RA Larson G.; RT "Enrichment of glycopeptides for glycan structure and attachment site RT identification."; RL Nat. Methods 6:809-811(2009). RN [38] RP FUNCTION, LRP1-BINDING, AND REGION. RX PubMed=20030366; DOI=10.1021/bi9017208; RA Guttman M., Prieto J.H., Croy J.E., Komives E.A.; RT "Decoding of lipoprotein-receptor interactions: properties of ligand RT binding modules governing interactions with apolipoprotein E."; RL Biochemistry 49:1207-1216(2010). RN [39] RP GLYCOSYLATION AT SER-308. RX PubMed=20511397; DOI=10.1074/mcp.m900430-mcp200; RA Lee Y., Kockx M., Raftery M.J., Jessup W., Griffith R., Kritharides L.; RT "Glycosylation and sialylation of macrophage-derived human apolipoprotein E RT analyzed by SDS-PAGE and mass spectrometry: evidence for a novel site of RT glycosylation on Ser290."; RL Mol. Cell. Proteomics 9:1968-1981(2010). RN [40] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [41] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22905912; DOI=10.1021/pr300539b; RA Rosenow A., Noben J.P., Jocken J., Kallendrusch S., Fischer-Posovszky P., RA Mariman E.C., Renes J.; RT "Resveratrol-induced changes of the human adipocyte secretion profile."; RL J. Proteome Res. 11:4733-4743(2012). RN [42] RP FUNCTION IN LIPOPROTEIN CLEARANCE, AND HEPARAN-SULFATE PROTEOGLYCANS RP BINDING. RX PubMed=23676495; DOI=10.1172/jci67398; RA Gonzales J.C., Gordts P.L., Foley E.M., Esko J.D.; RT "Apolipoproteins E and AV mediate lipoprotein clearance by hepatic RT proteoglycans."; RL J. Clin. Invest. 123:2742-2751(2013). RN [43] RP GLYCOSYLATION AT THR-26; THR-36 AND SER-314, AND IDENTIFICATION BY MASS RP SPECTROMETRY. RX PubMed=23234360; DOI=10.1021/pr300963h; RA Halim A., Ruetschi U., Larson G., Nilsson J.; RT "LC-MS/MS characterization of O-glycosylation sites and glycan structures RT of human cerebrospinal fluid glycoproteins."; RL J. Proteome Res. 12:573-584(2013). RN [44] RP FUNCTION IN CHOLESTEROL EFFLUX, AND INTERACTION WITH APP/A4 AMYLOID-BETA RP PEPTIDE. RX PubMed=23620513; DOI=10.1073/pnas.1220484110; RA Verghese P.B., Castellano J.M., Garai K., Wang Y., Jiang H., Shah A., RA Bu G., Frieden C., Holtzman D.M.; RT "ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/Abeta RT association in physiological conditions."; RL Proc. Natl. Acad. Sci. U.S.A. 110:E1807-E1816(2013). RN [45] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-147, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [46] RP INTERACTION WITH HCV ENVELOPE GLYCOPROTEIN E2 (MICROBIAL INFECTION), AND RP FUNCTION (MICROBIAL INFECTION). RX PubMed=25122793; DOI=10.1128/jvi.01660-14; RA Lee J.Y., Acosta E.G., Stoeck I.K., Long G., Hiet M.S., Mueller B., RA Fackler O.T., Kallis S., Bartenschlager R.; RT "Apolipoprotein E likely contributes to a maturation step of infectious RT hepatitis C virus particles and interacts with viral envelope RT glycoproteins."; RL J. Virol. 88:12422-12437(2014). RN [47] RP PHOSPHORYLATION AT SER-147. RX PubMed=26091039; DOI=10.1016/j.cell.2015.05.028; RA Tagliabracci V.S., Wiley S.E., Guo X., Kinch L.N., Durrant E., Wen J., RA Xiao J., Cui J., Nguyen K.B., Engel J.L., Coon J.J., Grishin N., RA Pinna L.A., Pagliarini D.J., Dixon J.E.; RT "A single kinase generates the majority of the secreted phosphoproteome."; RL Cell 161:1619-1632(2015). RN [48] RP SUBCELLULAR LOCATION, AND INTERACTION WITH PMEL. RX PubMed=26387950; DOI=10.1016/j.celrep.2015.08.057; RA van Niel G., Bergam P., Di Cicco A., Hurbain I., Lo Cicero A., Dingli F., RA Palmulli R., Fort C., Potier M.C., Schurgers L.J., Loew D., Levy D., RA Raposo G.; RT "Apolipoprotein E Regulates Amyloid Formation within Endosomes of Pigment RT Cells."; RL Cell Rep. 13:43-51(2015). RN [49] RP FUNCTION IN APP TRANSCRIPTION, AND CHARACTERIZATION OF VARIANT AD2 ARG-130. RX PubMed=28111074; DOI=10.1016/j.cell.2016.12.044; RA Huang Y.A., Zhou B., Wernig M., Suedhof T.C.; RT "ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and RT Abeta Secretion."; RL Cell 168:427-441(2017). RN [50] RP INTERACTION WITH HCV ENVELOPE GLYCOPROTEIN E2 (MICROBIAL INFECTION), AND RP FUNCTION (MICROBIAL INFECTION). RX PubMed=29695434; DOI=10.1128/jvi.00211-18; RA Kim J.Y., Ou J.J.; RT "Regulation of Apolipoprotein E Trafficking by Hepatitis C Virus-Induced RT Autophagy."; RL J. Virol. 92:e00211-e00218(2018). RN [51] RP FUNCTION, SUBCELLULAR LOCATION, AND ROLE IN TUMOR CELL INFILTRATION. RX PubMed=30333625; DOI=10.1038/s41586-018-0615-z; RA Deng M., Gui X., Kim J., Xie L., Chen W., Li Z., He L., Chen Y., Chen H., RA Luo W., Lu Z., Xie J., Churchill H., Xu Y., Zhou Z., Wu G., Yu C., John S., RA Hirayasu K., Nguyen N., Liu X., Huang F., Li L., Deng H., Tang H., RA Sadek A.H., Zhang L., Huang T., Zou Y., Chen B., Zhu H., Arase H., Xia N., RA Jiang Y., Collins R., You M.J., Homsi J., Unni N., Lewis C., Chen G.Q., RA Fu Y.X., Liao X.C., An Z., Zheng J., Zhang N., Zhang C.C.; RT "LILRB4 signalling in leukaemia cells mediates T cell suppression and RT tumour infiltration."; RL Nature 562:605-609(2018). RN [52] {ECO:0007744|PDB:1LPE} RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 41-184, FUNCTION, AND REGION. RX PubMed=2063194; DOI=10.1126/science.2063194; RA Wilson C., Wardell M.R., Weisgraber K.H., Mahley R.W., Agard D.A.; RT "Three-dimensional structure of the LDL receptor-binding domain of human RT apolipoprotein E."; RL Science 252:1817-1822(1991). RN [53] {ECO:0007744|PDB:1LE4} RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 41-184 OF VARIANT AD2 ARG-130, RP CHARACTERIZATION OF VARIANT AD2 ARG-130, MUTAGENESIS OF ARG-79 AND GLU-127, RP AND REGION. RX PubMed=8071364; DOI=10.1016/s0021-9258(17)31797-0; RA Dong L.M., Wilson C., Wardell M.R., Simmons T., Mahley R.W., RA Weisgraber K.H., Agard D.A.; RT "Human apolipoprotein E. Role of arginine 61 in mediating the lipoprotein RT preferences of the E3 and E4 isoforms."; RL J. Biol. Chem. 269:22358-22365(1994). RN [54] {ECO:0007744|PDB:1LE2} RP X-RAY CRYSTALLOGRAPHY (3.00 ANGSTROMS) OF 41-184 OF VARIANT CYS-176, AND RP CHARACTERIZATION OF VARIANT CYS-176. RX PubMed=7994571; DOI=10.1016/s0969-2126(00)00072-1; RA Wilson C., Mau T., Weisgraber K.H., Wardell M.R., Mahley R.W., Agard D.A.; RT "Salt bridge relay triggers defective LDL receptor binding by a mutant RT apolipoprotein."; RL Structure 2:713-718(1994). RN [55] {ECO:0007744|PDB:1NFN, ECO:0007744|PDB:1NFO} RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 19-209 OF VARIANT CYS-176, RP MUTAGENESIS OF ASP-172, CHARACTERIZATION OF VARIANT CYS-176, FUNCTION, AND RP LDLR-BINDING. RX PubMed=8756331; DOI=10.1038/nsb0896-718; RA Dong L.-M., Parkin S., Trakhanov S.D., Rupp B., Simmons T., Arnold K.S., RA Newhouse Y.M., Innerarity T.L., Weisgraber K.H.; RT "Novel mechanism for defective receptor binding of apolipoprotein E2 in RT type III hyperlipoproteinemia."; RL Nat. Struct. Biol. 3:718-722(1996). RN [56] {ECO:0007744|PDB:1BZ4, ECO:0007744|PDB:1OR2, ECO:0007744|PDB:1OR3} RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 19-183. RX PubMed=10850798; DOI=10.1110/ps.9.5.886; RA Segelke B.W., Forstner M., Knapp M., Trakhanov S.D., Parkin S., RA Newhouse Y.M., Bellamy H.D., Weisgraber K.H., Rupp B.; RT "Conformational flexibility in the apolipoprotein E amino-terminal domain RT structure determined from three new crystal forms: implications for lipid RT binding."; RL Protein Sci. 9:886-897(2000). RN [57] {ECO:0007744|PDB:1B68} RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 19-209 OF VARIANT AD2 ARG-130. RX PubMed=11258893; DOI=10.1021/bi002417n; RA Dong J., Peters-Libeu C.A., Weisgraber K.H., Segelke B.W., Rupp B., RA Capila I., Hernaiz M.J., LeBrun L.A., Linhardt R.J.; RT "Interaction of the N-terminal domain of apolipoprotein E4 with heparin."; RL Biochemistry 40:2826-2834(2001). RN [58] {ECO:0007744|PDB:2KNY} RP STRUCTURE BY NMR OF 147-167 IN COMPLEX WITH LRP1, FUNCTION, AND RP LRP1-BINDING. RX PubMed=20303980; DOI=10.1016/j.jmb.2010.03.022; RA Guttman M., Prieto J.H., Handel T.M., Domaille P.J., Komives E.A.; RT "Structure of the minimal interface between ApoE and LRP."; RL J. Mol. Biol. 398:306-319(2010). RN [59] RP VARIANT HLPP3 262-GLU-GLU-263 DELINS LYS-LYS. RX PubMed=2738044; DOI=10.1093/oxfordjournals.jbchem.a122618; RA Maeda H., Nakamura H., Kobori S., Okada M., Mori H., Niki H., Ogura T., RA Hiraga S.; RT "Identification of human apolipoprotein E variant gene: apolipoprotein E7 RT (Glu244,245----Lys244,245)."; RL J. Biochem. 105:51-54(1989). RN [60] RP VARIANT LYS-21. RX PubMed=2760009; DOI=10.1093/oxfordjournals.jbchem.a122692; RA Maeda H., Nakamura H., Kobori S., Okada M., Niki H., Ogura T., Hiraga S.; RT "Molecular cloning of a human apolipoprotein E variant: E5 (Glu-3-->Lys)."; RL J. Biochem. 105:491-493(1989). RN [61] RP VARIANTS HLPP3 ARG-130 AND GLU-VAL-GLN-ALA-MET-LEU-GLY-145 INS. RX PubMed=2556398; DOI=10.1016/s0021-9258(19)30067-5; RA Wardell M.R., Weisgraber K.H., Havekes L.M., Rall S.C. Jr.; RT "Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a RT tandem repeat of residues 121-127."; RL J. Biol. Chem. 264:21205-21210(1989). RN [62] RP VARIANT HLPP3 HIS-163. RX PubMed=2101409; DOI=10.2169/internalmedicine1962.29.587; RA Suehiro T., Yoshida K., Yamano T., Ohno F.; RT "Identification and characterization of a new variant of apolipoprotein E RT (apo E-Kochi)."; RL Jpn. J. Med. 29:587-594(1990). RN [63] RP VARIANT CYS-246. RX PubMed=2341812; RA Wardell M.R., Rall S.C. Jr., Brennan S.O., Nye E.R., George P.M., RA Janus E.D., Weisgraber K.H.; RT "Apolipoprotein E2-Dunedin (228 Arg replaced by Cys): an apolipoprotein E2 RT variant with normal receptor-binding activity."; RL J. Lipid Res. 31:535-543(1990). RN [64] RP VARIANT HLPP3 GLN-164. RX PubMed=2313204; RA Smit M., de Knijff P., van der Kooij-Meijs E., Groenendijk C., RA van den Maagdenberg A.M., Gevers Leuven J.A., Stalenhoef A.F., Stuyt P.M., RA Frants R.R., Havekes L.M.; RT "Genetic heterogeneity in familial dysbetalipoproteinemia. The RT E2(lys146----gln) variant results in a dominant mode of inheritance."; RL J. Lipid Res. 31:45-53(1990). RN [65] RP VARIANTS HLPP3 LYS-31 AND CYS-163. RX PubMed=1674745; DOI=10.1016/s0021-9258(18)99249-5; RA Lohse P., Mann W.A., Stein E.A., Brewer H.B. Jr.; RT "Apolipoprotein E-4 Philadelphia (Glu-13-->Lys,Arg-145-->Cys). Homozygosity RT for two rare point mutations in the apolipoprotein E gene combined with RT severe type III hyperlipoproteinemia."; RL J. Biol. Chem. 266:10479-10484(1991). RN [66] RP VARIANT APOE5 FRENCH-CANADIAN LYS-31. RX PubMed=1713245; RA Mailly F., Xu C.F., Xhignesse M., Lussier-Cacan S., Talmud P.J., RA Davignon J., Humphries S.E., Nestruck A.C.; RT "Characterization of a new apolipoprotein E5 variant detected in two RT French-Canadian subjects."; RL J. Lipid Res. 32:613-620(1991). RN [67] RP CHARACTERIZATION OF VARIANT LYS-21, FUNCTION, AND LDLR-BINDING. RX PubMed=1530612; DOI=10.1016/0006-291x(92)91321-g; RA Dong L.M., Yamamura T., Tajima S., Yamamoto A.; RT "Site-directed mutagenesis of an apolipoprotein E mutant, apo E5(Glu3---- RT Lys) and its binding to low density lipoprotein receptors."; RL Biochem. Biophys. Res. Commun. 187:1180-1186(1992). RN [68] RP VARIANT HLPP3 228-TRP--HIS-317 DEL. RX PubMed=1361196; RA Lohse P., Brewer H.B. III, Meng M.S., Skarlatos S.I., LaRosa J.C., RA Brewer H.B. Jr.; RT "Familial apolipoprotein E deficiency and type III hyperlipoproteinemia due RT to a premature stop codon in the apolipoprotein E gene."; RL J. Lipid Res. 33:1583-1590(1992). RN [69] RP VARIANTS GLU-254; GLY-269; GLU-270; HIS-292 AND ARG-314. RX PubMed=8488843; RA van den Maagdenberg A.M.J.M., Weng W., de Bruijn I.H., de Knijff P., RA Funke H., Smelt A.H.M., Leuven J.A.G., van 't Hooft F.M., Assmann G., RA Hofker M.H., Havekes L.M., Frants R.R.; RT "Characterization of five new mutants in the carboxyl-terminal domain of RT human apolipoprotein E: no cosegregation with severe hyperlipidemia."; RL Am. J. Hum. Genet. 52:937-946(1993). RN [70] RP VARIANTS LYS-99 AND ARG-130. RX PubMed=8125051; DOI=10.1002/elps.11501401164; RA Ruzicka V., Maerz W., Russ A., Fisher E., Mondorf W., Gross W.; RT "Characterization of the gene for apolipoprotein E5-Frankfurt (Gln81->Lys, RT Cys112->Arg) by polymerase chain reaction, restriction isotyping, and RT temperature gradient gel electrophoresis."; RL Electrophoresis 14:1032-1037(1993). RN [71] RP CHARACTERIZATION OF VARIANT GLU-VAL-GLN-ALA-MET-LEU-GLY-145 INS. RX PubMed=8468528; RA Fazio S., Horie Y., Weisgraber K.H., Havekes L.M., Rall S.C. Jr.; RT "Preferential association of apolipoprotein E Leiden with very low density RT lipoproteins of human plasma."; RL J. Lipid Res. 34:447-453(1993). RN [72] RP INVOLVEMENT IN AD2, AND VARIANT AD2 ARG-130. RX PubMed=8346443; DOI=10.1126/science.8346443; RA Corder E.H., Saunders A.M., Strittmatter W.J., Schmechel D.E., RA Gaskell P.C., Small G.W., Roses A.D., Haines J.L., Pericak-Vance M.A.; RT "Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's RT disease in late onset families."; RL Science 261:921-923(1993). RN [73] RP VARIANTS HLPP3 ARG-130; SER-154; CYS-160 AND CYS-176, AND VARIANT ASP-145. RX PubMed=8287539; RA Richard P., Thomas G., de Zulueta M.P., de Gennes J.-L., Thomas M., RA Cassaigne A., Bereziat G., Iron A.; RT "Common and rare genotypes of human apolipoprotein E determined by specific RT restriction profiles of polymerase chain reaction-amplified DNA."; RL Clin. Chem. 40:24-29(1994). RN [74] RP VARIANTS HLPP3 LYS-31; ARG-130 AND CYS-154, AND VARIANTS ARG-102 AND RP GLN-152. RX PubMed=7833947; DOI=10.1002/humu.1380040303; RA de Knijff P., van den Maagdenberg A.M.J.M., Frants R.R., Havekes L.M.; RT "Genetic heterogeneity of apolipoprotein E and its influence on plasma RT lipid and lipoprotein levels."; RL Hum. Mutat. 4:178-194(1994). RN [75] RP VARIANT HLPP3 GLU-164, CHARACTERIZATION OF VARIANT HLPP3 GLU-164 AND RP CYS-176, FUNCTION, LDLR-BINDING, AND HEPARIN-BINDING. RX PubMed=7635945; DOI=10.1172/jci118096; RA Mann W.A., Lohse P., Gregg R.E., Ronan R., Hoeg J.M., Zech L.A., RA Brewer H.B. Jr.; RT "Dominant expression of type III hyperlipoproteinemia. Pathophysiological RT insights derived from the structural and kinetic characteristics of ApoE-1 RT (Lys146-->Glu)."; RL J. Clin. Invest. 96:1100-1107(1995). RN [76] RP VARIANT GLN-242. RX PubMed=8664327; DOI=10.1016/0005-2760(96)00014-8; RA Moriyama K., Sasaki J., Takada Y., Arakawa F., Matsunaga A., Ito Y., RA Arakawa K.; RT "Characterization of a novel variant of apolipoprotein E, E2 Fukuoka (Arg- RT 224 --> Gln) in a hyperlipidemic patient with xanthomatosis."; RL Biochim. Biophys. Acta 1301:185-190(1996). RN [77] RP VARIANT LPG PRO-163. RX PubMed=9176854; DOI=10.1681/asn.v85820; RA Oikawa S., Matsunaga A., Saito T., Sato H., Seki T., Hoshi K., Hayasaka K., RA Kotake H., Midorikawa H., Sekikawa A., Hara S., Abe K., Toyota T., RA Jingami H., Nakamura H., Sasaki J.; RT "Apolipoprotein E Sendai (arginine 145-->proline): a new variant associated RT with lipoprotein glomerulopathy."; RL J. Am. Soc. Nephrol. 8:820-823(1997). RN [78] RP VARIANTS ARG-130 AND GLY-269. RX PubMed=9360638; DOI=10.1016/s1383-5726(97)00009-5; RA Kang A.K., Jenkins D.J.A., Wolever T.M.S., Huff M.W., Maguire G.F., RA Connelly P.W., Hegele R.A.; RT "Apolipoprotein E R112; R251G: a carboxy-terminal variant found in patients RT with hyperlipidemia and coronary heart disease."; RL Mutat. Res. 382:57-65(1997). RN [79] RP VARIANT LPG CYS-43. RX PubMed=10432380; DOI=10.1046/j.1523-1755.1999.00572.x; RA Matsunaga A., Sasaki J., Komatsu T., Kanatsu K., Tsuji E., Moriyama K., RA Koga T., Arakawa K., Oikawa S., Saito T., Kita T., Doi T.; RT "A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein RT glomerulopathy."; RL Kidney Int. 56:421-427(1999). RN [80] RP CHARACTERIZATION OF VARIANT LPG PRO-163, AND CHARACTERIZATION OF VARIANT RP AD2 ARG-130. RX PubMed=10903326; DOI=10.1074/jbc.m005906200; RA Ishigaki Y., Oikawa S., Suzuki T., Usui S., Magoori K., Kim D.H., RA Suzuki H., Sasaki J., Sasano H., Okazaki M., Toyota T., Saito T., RA Yamamoto T.T.; RT "Virus-mediated transduction of apolipoprotein E (ApoE)-sendai develops RT lipoprotein glomerulopathy in ApoE-deficient mice."; RL J. Biol. Chem. 275:31269-31273(2000). RN [81] RP VARIANT SBHD LEU-167 DEL. RX PubMed=11095479; DOI=10.1210/jcem.85.11.6981; RA Nguyen T.T., Kruckeberg K.E., O'Brien J.F., Ji Z.-S., Karnes P.S., RA Crotty T.B., Hay I.D., Mahley R.W., O'Brien T.; RT "Familial splenomegaly: macrophage hypercatabolism of lipoproteins RT associated with apolipoprotein E mutation [apolipoprotein E (delta149 RT Leu)]."; RL J. Clin. Endocrinol. Metab. 85:4354-4358(2000). RN [82] RP VARIANT VAL-124. RX PubMed=12864777; DOI=10.1046/j.1365-2362.2003.01180.x; RA Miserez A.R., Scharnagl H., Muller P.Y., Mirsaidi R., Stahelin H.B., RA Monsch A., Marz W., Hoffmann M.M.; RT "Apolipoprotein E3Basel: new insights into a highly conserved protein RT region."; RL Eur. J. Clin. Invest. 33:677-685(2003). RN [83] RP VARIANTS ARG-130 AND CYS-176. RX PubMed=12966036; DOI=10.1093/hmg/ddg314; RA Morabia A., Cayanis E., Costanza M.C., Ross B.M., Flaherty M.S., RA Alvin G.B., Das K., Gilliam T.C.; RT "Association of extreme blood lipid profile phenotypic variation with 11 RT reverse cholesterol transport genes and 10 non-genetic cardiovascular RT disease risk factors."; RL Hum. Mol. Genet. 12:2733-2743(2003). RN [84] RP VARIANT SBHD LEU-167 DEL. RX PubMed=16094309; DOI=10.1038/sj.ejhg.5201480; RA Faivre L., Saugier-Veber P., Pais de Barros J.-P., Verges B., Couret B., RA Lorcerie B., Thauvin C., Charbonnier F., Huet F., Gambert P., Frebourg T., RA Duvillard L.; RT "Variable expressivity of the clinical and biochemical phenotype associated RT with the apolipoprotein E p.Leu149del mutation."; RL Eur. J. Hum. Genet. 13:1186-1191(2005). RN [85] RP VARIANT LPG CYS-43. RX PubMed=18077821; DOI=10.1056/nejmc072088; RA Rovin B.H., Roncone D., McKinley A., Nadasdy T., Korbet S.M., RA Schwartz M.M.; RT "APOE Kyoto mutation in European Americans with lipoprotein RT glomerulopathy."; RL N. Engl. J. Med. 357:2522-2524(2007). RN [86] RP VARIANT HIS-64, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=22028381; DOI=10.1093/jmcb/mjr024; RA Su Z.D., Sun L., Yu D.X., Li R.X., Li H.X., Yu Z.J., Sheng Q.H., Lin X., RA Zeng R., Wu J.R.; RT "Quantitative detection of single amino acid polymorphisms by targeted RT proteomics."; RL J. Mol. Cell Biol. 3:309-315(2011). RN [87] RP VARIANT HLPP3 SER-154, AND VARIANT SBHD LEU-167 DEL. RX PubMed=22481068; DOI=10.1016/j.atherosclerosis.2012.03.011; RA Solanas-Barca M., de Castro-Oros I., Mateo-Gallego R., Cofan M., Plana N., RA Puzo J., Burillo E., Martin-Fuentes P., Ros E., Masana L., Pocovi M., RA Civeira F., Cenarro A.; RT "Apolipoprotein E gene mutations in subjects with mixed hyperlipidemia and RT a clinical diagnosis of familial combined hyperlipidemia."; RL Atherosclerosis 222:449-455(2012). RN [88] RP VARIANT SBHD LEU-167 DEL. RX PubMed=24267230; DOI=10.1016/j.atherosclerosis.2013.09.007; RA Awan Z., Choi H.Y., Stitziel N., Ruel I., Bamimore M.A., Husa R., RA Gagnon M.H., Wang R.H., Peloso G.M., Hegele R.A., Seidah N.G., RA Kathiresan S., Genest J.; RT "APOE p.Leu167del mutation in familial hypercholesterolemia."; RL Atherosclerosis 231:218-222(2013). RN [89] RP VARIANT SBHD LEU-167 DEL. RX PubMed=22949395; DOI=10.1002/humu.22215; RA Marduel M., Ouguerram K., Serre V., Bonnefont-Rousselot D., RA Marques-Pinheiro A., Erik Berge K., Devillers M., Luc G., Lecerf J.M., RA Tosolini L., Erlich D., Peloso G.M., Stitziel N., Nitchke P., Jais J.P., RA Abifadel M., Kathiresan S., Leren T.P., Rabes J.P., Boileau C., Varret M.; RT "Description of a large family with autosomal dominant hypercholesterolemia RT associated with the APOE p.Leu167del mutation."; RL Hum. Mutat. 34:83-87(2013). RN [90] RP VARIANTS PRO-46 AND ASP-145, VARIANT HLPP3 CYS-163, AND VARIANT SBHD RP LEU-167 DEL. RX PubMed=26802169; DOI=10.1194/jlr.p055699; RA Wintjens R., Bozon D., Belabbas K., Mbou F., Girardet J.P., Tounian P., RA Jolly M., Boccara F., Cohen A., Karsenty A., Dubern B., Carel J.C., RA Azar-Kolakez A., Feillet F., Labarthe F., Gorsky A.M., Horovitz A., RA Tamarindi C., Kieffer P., Lienhardt A., Lascols O., Di Filippo M., RA Dufernez F.; RT "Global molecular analysis and APOE mutations in a cohort of autosomal RT dominant hypercholesterolemia patients in France."; RL J. Lipid Res. 57:482-491(2016). RN [91] RP REVIEW, POLYMORPHISM, AND TISSUE SPECIFICITY. RX PubMed=25173806; DOI=10.1016/j.nbd.2014.08.025; RA Huang Y., Mahley R.W.; RT "Apolipoprotein E: structure and function in lipid metabolism, RT neurobiology, and Alzheimer's diseases."; RL Neurobiol. Dis. 72:3-12(2014). RN [92] RP REVIEW, FUNCTION, AND PTM. RX PubMed=29516132; DOI=10.1007/s00109-018-1632-y; RA Kockx M., Traini M., Kritharides L.; RT "Cell-specific production, secretion, and function of apolipoprotein E."; RL J. Mol. Med. 96:361-371(2018). RN [93] RP POLYMORPHISM, AND VARIANT ARG-130. RX PubMed=33450186; DOI=10.1016/j.stem.2020.12.018; RA Wang C., Zhang M., Garcia G. Jr., Tian E., Cui Q., Chen X., Sun G., RA Wang J., Arumugaswami V., Shi Y.; RT "ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response."; RL Cell Stem Cell 0:0-0(2021). CC -!- FUNCTION: APOE is an apolipoprotein, a protein associating with lipid CC particles, that mainly functions in lipoprotein-mediated lipid CC transport between organs via the plasma and interstitial fluids CC (PubMed:14754908, PubMed:1911868, PubMed:6860692). APOE is a core CC component of plasma lipoproteins and is involved in their production, CC conversion and clearance (PubMed:14754908, PubMed:1911868, CC PubMed:1917954, PubMed:23620513, PubMed:2762297, PubMed:6860692, CC PubMed:9395455). Apolipoproteins are amphipathic molecules that CC interact both with lipids of the lipoprotein particle core and the CC aqueous environment of the plasma (PubMed:2762297, PubMed:6860692, CC PubMed:9395455). As such, APOE associates with chylomicrons, CC chylomicron remnants, very low density lipoproteins (VLDL) and CC intermediate density lipoproteins (IDL) but shows a preferential CC binding to high-density lipoproteins (HDL) (PubMed:1911868, CC PubMed:6860692). It also binds a wide range of cellular receptors CC including the LDL receptor/LDLR, the LDL receptor-related proteins CC LRP1, LRP2 and LRP8 and the very low-density lipoprotein receptor/VLDLR CC that mediate the cellular uptake of the APOE-containing lipoprotein CC particles (PubMed:12950167, PubMed:1530612, PubMed:1917954, CC PubMed:20030366, PubMed:20303980, PubMed:2063194, PubMed:2762297, CC PubMed:7635945, PubMed:7768901, PubMed:8756331, PubMed:8939961). CC Finally, APOE also has a heparin-binding activity and binds heparan- CC sulfate proteoglycans on the surface of cells, a property that supports CC the capture and the receptor-mediated uptake of APOE-containing CC lipoproteins by cells (PubMed:23676495, PubMed:7635945, PubMed:9395455, CC PubMed:9488694). A main function of APOE is to mediate lipoprotein CC clearance through the uptake of chylomicrons, VLDLs, and HDLs by CC hepatocytes (PubMed:1911868, PubMed:1917954, PubMed:23676495, CC PubMed:29516132, PubMed:9395455). APOE is also involved in the CC biosynthesis by the liver of VLDLs as well as their uptake by CC peripheral tissues ensuring the delivery of triglycerides and energy CC storage in muscle, heart and adipose tissues (PubMed:2762297, CC PubMed:29516132). By participating in the lipoprotein-mediated CC distribution of lipids among tissues, APOE plays a critical role in CC plasma and tissues lipid homeostasis (PubMed:1917954, PubMed:2762297, CC PubMed:29516132). APOE is also involved in two steps of reverse CC cholesterol transport, the HDLs-mediated transport of cholesterol from CC peripheral tissues to the liver, and thereby plays an important role in CC cholesterol homeostasis (PubMed:14754908, PubMed:23620513, CC PubMed:9395455). First, it is functionally associated with ABCA1 in the CC biogenesis of HDLs in tissues (PubMed:14754908, PubMed:23620513). CC Second, it is enriched in circulating HDLs and mediates their uptake by CC hepatocytes (PubMed:9395455). APOE also plays an important role in CC lipid transport in the central nervous system, regulating neuron CC survival and sprouting (PubMed:25173806, PubMed:8939961). APOE is also CC involved in innate and adaptive immune responses, controlling for CC instance the survival of myeloid-derived suppressor cells (By CC similarity). Binds to the immune cell receptor LILRB4 CC (PubMed:30333625). APOE may also play a role in transcription CC regulation through a receptor-dependent and cholesterol-independent CC mechanism, that activates MAP3K12 and a non-canonical MAPK signal CC transduction pathway that results in enhanced AP-1-mediated CC transcription of APP (PubMed:28111074). {ECO:0000250|UniProtKB:P08226, CC ECO:0000269|PubMed:12950167, ECO:0000269|PubMed:14754908, CC ECO:0000269|PubMed:1530612, ECO:0000269|PubMed:1911868, CC ECO:0000269|PubMed:1917954, ECO:0000269|PubMed:20030366, CC ECO:0000269|PubMed:20303980, ECO:0000269|PubMed:2063194, CC ECO:0000269|PubMed:23620513, ECO:0000269|PubMed:23676495, CC ECO:0000269|PubMed:2762297, ECO:0000269|PubMed:28111074, CC ECO:0000269|PubMed:30333625, ECO:0000269|PubMed:6860692, CC ECO:0000269|PubMed:7635945, ECO:0000269|PubMed:7768901, CC ECO:0000269|PubMed:8756331, ECO:0000269|PubMed:8939961, CC ECO:0000269|PubMed:9395455, ECO:0000269|PubMed:9488694, CC ECO:0000303|PubMed:25173806, ECO:0000303|PubMed:29516132}. CC -!- FUNCTION: (Microbial infection) Through its interaction with HCV CC envelope glycoprotein E2, participates in the attachment of HCV to CC HSPGs and other receptors (LDLr, VLDLr, and SR-B1) on the cell surface CC and to the assembly, maturation and infectivity of HCV viral particles CC (PubMed:25122793, PubMed:29695434). This interaction is probably CC promoted via the up-regulation of cellular autophagy by the virus CC (PubMed:29695434). {ECO:0000269|PubMed:25122793, CC ECO:0000269|PubMed:29695434}. CC -!- SUBUNIT: Homotetramer (PubMed:8340399). May interact with ABCA1; CC functionally associated with ABCA1 in the biogenesis of HDLs CC (PubMed:14754908). May interact with APP/A4 amyloid-beta peptide; the CC interaction is extremely stable in vitro but its physiological CC significance is unclear (PubMed:23620513, PubMed:8367470). May interact CC with MAPT (PubMed:7972031). May interact with MAP2 (PubMed:7891887). In CC the cerebrospinal fluid, interacts with secreted SORL1 CC (PubMed:30448281). Interacts with PMEL; this allows the loading of PMEL CC luminal fragment on ILVs to induce fibril nucleation. CC {ECO:0000269|PubMed:14754908, ECO:0000269|PubMed:23620513, CC ECO:0000269|PubMed:26387950, ECO:0000269|PubMed:30448281, CC ECO:0000269|PubMed:7891887, ECO:0000269|PubMed:7972031, CC ECO:0000269|PubMed:8340399, ECO:0000269|PubMed:8367470}. CC -!- SUBUNIT: (Microbial infection) Interacts with hepatitis C virus (HCV) CC envelope glycoprotein E2; this interaction is required for HCV CC infectivity and production. {ECO:0000269|PubMed:25122793, CC ECO:0000269|PubMed:29695434}. CC -!- INTERACTION: CC P02649; Q9UIJ7: AK3; NbExp=3; IntAct=EBI-1222467, EBI-3916527; CC P02649; Q06481-5: APLP2; NbExp=3; IntAct=EBI-1222467, EBI-25646567; CC P02649; PRO_0000000093 [P05067]: APP; NbExp=4; IntAct=EBI-1222467, EBI-2431589; CC P02649; Q9HBG4: ATP6V0A4; NbExp=3; IntAct=EBI-1222467, EBI-25832286; CC P02649; Q9NUB4: C20orf141; NbExp=3; IntAct=EBI-1222467, EBI-9088162; CC P02649; P02748: C9; NbExp=2; IntAct=EBI-1222467, EBI-6677628; CC P02649; Q16543: CDC37; NbExp=3; IntAct=EBI-1222467, EBI-295634; CC P02649; P08603: CFH; NbExp=8; IntAct=EBI-1222467, EBI-1223708; CC P02649; Q9UBD9: CLCF1; NbExp=3; IntAct=EBI-1222467, EBI-2880701; CC P02649; Q8IUW6: CLSTN3; NbExp=3; IntAct=EBI-1222467, EBI-25832219; CC P02649; P26441: CNTF; NbExp=3; IntAct=EBI-1222467, EBI-1050897; CC P02649; Q9H6J7-2: CSTPP1; NbExp=3; IntAct=EBI-1222467, EBI-13328871; CC P02649; Q9H816: DCLRE1B; NbExp=3; IntAct=EBI-1222467, EBI-3508943; CC P02649; Q9BQ95: ECSIT; NbExp=4; IntAct=EBI-1222467, EBI-712452; CC P02649; Q9Y6C2-2: EMILIN1; NbExp=3; IntAct=EBI-1222467, EBI-11748557; CC P02649; Q3SYB3: FOXD4L6; NbExp=3; IntAct=EBI-1222467, EBI-6425864; CC P02649; Q8IY40: GRIK2; NbExp=3; IntAct=EBI-1222467, EBI-25832107; CC P02649; O75409: H2AP; NbExp=3; IntAct=EBI-1222467, EBI-6447217; CC P02649; P00738: HP; NbExp=7; IntAct=EBI-1222467, EBI-1220767; CC P02649; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-1222467, EBI-1108377; CC P02649; P01130: LDLR; NbExp=4; IntAct=EBI-1222467, EBI-988319; CC P02649; P09382: LGALS1; NbExp=3; IntAct=EBI-1222467, EBI-1048875; CC P02649; Q07954: LRP1; NbExp=23; IntAct=EBI-1222467, EBI-1046087; CC P02649; Q14114: LRP8; NbExp=2; IntAct=EBI-1222467, EBI-2681187; CC P02649; Q14114-3: LRP8; NbExp=3; IntAct=EBI-1222467, EBI-25832196; CC P02649; P11137-4: MAP2; NbExp=3; IntAct=EBI-1222467, EBI-25832133; CC P02649; P10636-6: MAPT; NbExp=3; IntAct=EBI-1222467, EBI-7796455; CC P02649; Q9Y3D2: MSRB2; NbExp=3; IntAct=EBI-1222467, EBI-9092052; CC P02649; P02795: MT2A; NbExp=3; IntAct=EBI-1222467, EBI-996616; CC P02649; Q53EL6: PDCD4; NbExp=3; IntAct=EBI-1222467, EBI-935824; CC P02649; Q9NS23-4: RASSF1; NbExp=3; IntAct=EBI-1222467, EBI-438710; CC P02649; P52756: RBM5; NbExp=3; IntAct=EBI-1222467, EBI-714003; CC P02649; Q6ZNA4-2: RNF111; NbExp=3; IntAct=EBI-1222467, EBI-21535400; CC P02649; Q8WTV0-2: SCARB1; NbExp=3; IntAct=EBI-1222467, EBI-21529758; CC P02649; P37840: SNCA; NbExp=11; IntAct=EBI-1222467, EBI-985879; CC P02649; Q8IUW3: SPATA2L; NbExp=3; IntAct=EBI-1222467, EBI-2510414; CC P02649; P50502: ST13; NbExp=3; IntAct=EBI-1222467, EBI-357285; CC P02649; O75069: TMCC2; NbExp=5; IntAct=EBI-1222467, EBI-726731; CC P02649; Q13829: TNFAIP1; NbExp=3; IntAct=EBI-1222467, EBI-2505861; CC P02649; Q9NZC2: TREM2; NbExp=4; IntAct=EBI-1222467, EBI-14036387; CC P02649; Q6PID6: TTC33; NbExp=3; IntAct=EBI-1222467, EBI-2555404; CC P02649; Q8TBC4: UBA3; NbExp=3; IntAct=EBI-1222467, EBI-717567; CC P02649; Q9NYH9: UTP6; NbExp=3; IntAct=EBI-1222467, EBI-749211; CC P02649; P21796: VDAC1; NbExp=2; IntAct=EBI-1222467, EBI-354158; CC P02649; P17028: ZNF24; NbExp=3; IntAct=EBI-1222467, EBI-707773; CC P02649; PRO_0000037570 [P27958]; Xeno; NbExp=4; IntAct=EBI-1222467, EBI-6904269; CC PRO_0000001987; P10636: MAPT; NbExp=3; IntAct=EBI-9209835, EBI-366182; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:2498325, CC ECO:0000269|PubMed:30333625}. Secreted, extracellular space CC {ECO:0000269|PubMed:8340399}. Secreted, extracellular space, CC extracellular matrix {ECO:0000269|PubMed:9488694}. Extracellular CC vesicle {ECO:0000269|PubMed:26387950}. Endosome, multivesicular body CC {ECO:0000269|PubMed:26387950}. Note=In the plasma, APOE is associated CC with chylomicrons, chylomicrons remnants, VLDL, LDL and HDL CC lipoproteins (PubMed:1911868, PubMed:8340399). Lipid poor oligomeric CC APOE is associated with the extracellular matrix in a calcium- and CC heparan-sulfate proteoglycans-dependent manner (PubMed:9488694). CC Lipidation induces the release from the extracellular matrix CC (PubMed:9488694). Colocalizes with CD63 and PMEL at exosomes and in CC intraluminal vesicles within multivesicular endosomes. CC {ECO:0000269|PubMed:1911868, ECO:0000269|PubMed:26387950, CC ECO:0000269|PubMed:8340399, ECO:0000269|PubMed:9488694}. CC -!- TISSUE SPECIFICITY: Produced by several tissues and cell types and CC mainly found associated with lipid particles in the plasma, the CC interstitial fluid and lymph (PubMed:25173806). Mainly synthesized by CC liver hepatocytes (PubMed:25173806). Significant quantities are also CC produced in brain, mainly by astrocytes and glial cells in the cerebral CC cortex, but also by neurons in frontal cortex and hippocampus CC (PubMed:10027417, PubMed:3115992). It is also expressed by cells of the CC peripheral nervous system (PubMed:10027417, PubMed:25173806). Also CC expressed by adrenal gland, testis, ovary, skin, kidney, spleen and CC adipose tissue and macrophages in various tissues (PubMed:25173806). CC {ECO:0000269|PubMed:10027417, ECO:0000269|PubMed:3115992, CC ECO:0000303|PubMed:25173806}. CC -!- PTM: APOE exists as multiple glycosylated and sialylated glycoforms CC within cells and in plasma (PubMed:29516132). The extent of CC glycosylation and sialylation are tissue and context specific CC (PubMed:29516132). Plasma APOE undergoes desialylation and is less CC glycosylated and sialylated than the cellular form (PubMed:19838169, CC PubMed:20511397, PubMed:23234360, PubMed:2498325). Glycosylation is not CC required for proper expression and secretion (PubMed:2498325). O- CC glycosylated with core 1 or possibly core 8 glycans. Thr-307 and Ser- CC 314 are minor glycosylation sites compared to Ser-308 (PubMed:19838169, CC PubMed:23234360). {ECO:0000269|PubMed:19838169, CC ECO:0000269|PubMed:20511397, ECO:0000269|PubMed:23234360, CC ECO:0000269|PubMed:2498325, ECO:0000303|PubMed:29516132}. CC -!- PTM: Glycated in plasma VLDL of normal subjects, and of hyperglycemic CC diabetic patients at a higher level (2-3 fold). CC {ECO:0000269|PubMed:10452964}. CC -!- PTM: Phosphorylated by FAM20C in the extracellular medium. CC {ECO:0000269|PubMed:26091039}. CC -!- PTM: Undergoes C-terminal proteolytic processing in neurons. C- CC terminally truncated APOE has a tendency to form neurotoxic CC intracellular neurofibrillary tangle-like inclusions in neurons. CC {ECO:0000269|PubMed:11447277}. CC -!- POLYMORPHISM: There are three common APOE alleles identified: CC APOE*2/APOE-epsilon2/E2, APOE*3/APOE-epsilon3/E3, and APOE*4/APOE- CC epsilon4/E4. The corresponding ApoE2, ApoE3 and ApoE4 isoforms CC differentially present Cys and Arg residues at positions 130 and 176. CC The most common allele in the human population is APOE*3 which sequence CC is the one displayed in that entry with a Cys at position 130 and an CC Arg at position 176. Common APOE variants influence lipoprotein CC metabolism in healthy individuals. Additional variants have been CC described and are described relative to the three common alleles. CC Allele APOE*4 is strongly associated with risk for severe COVID-19, CC increases susceptibility to SARS-CoV-2 infection in neurons and CC astrocytes (PubMed:33450186). {ECO:0000269|PubMed:2987927, CC ECO:0000269|PubMed:3243553, ECO:0000269|PubMed:33450186, CC ECO:0000269|PubMed:6325438, ECO:0000303|PubMed:25173806}. CC -!- DISEASE: Hyperlipoproteinemia 3 (HLPP3) [MIM:617347]: A disorder CC characterized by the accumulation of intermediate-density lipoprotein CC particles (IDL or broad-beta-lipoprotein) rich in cholesterol. Clinical CC features include xanthomas, yellowish lipid deposits in the palmar CC crease, or less specific on tendons and on elbows. The disorder rarely CC manifests before the third decade in men. In women, it is usually CC expressed only after the menopause. {ECO:0000269|PubMed:1361196, CC ECO:0000269|PubMed:1674745, ECO:0000269|PubMed:2101409, CC ECO:0000269|PubMed:22481068, ECO:0000269|PubMed:2313204, CC ECO:0000269|PubMed:2556398, ECO:0000269|PubMed:26802169, CC ECO:0000269|PubMed:2738044, ECO:0000269|PubMed:7635945, CC ECO:0000269|PubMed:7833947, ECO:0000269|PubMed:8287539}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. The vast majority of the patients are homozygous for APOE*2 CC alleles. More severe cases of HLPP3 have also been observed in CC individuals heterozygous for rare APOE variants. The influence of APOE CC on lipid levels is often suggested to have major implications for the CC risk of coronary artery disease (CAD). Individuals carrying the common CC APOE*4 variant are at higher risk of CAD. CC -!- DISEASE: Alzheimer disease 2 (AD2) [MIM:104310]: A late-onset form of CC Alzheimer disease. Alzheimer disease is a neurodegenerative disorder CC characterized by progressive dementia, loss of cognitive abilities, and CC deposition of fibrillar amyloid proteins as intraneuronal CC neurofibrillary tangles, extracellular amyloid plaques and vascular CC amyloid deposits. The major constituents of these plaques are CC neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that CC are produced by the proteolysis of the transmembrane APP protein. The CC cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, CC such as C31, are also implicated in neuronal death. CC {ECO:0000269|PubMed:10903326, ECO:0000269|PubMed:11258893, CC ECO:0000269|PubMed:11447277, ECO:0000269|PubMed:28111074, CC ECO:0000269|PubMed:2987927, ECO:0000269|PubMed:7891887, CC ECO:0000269|PubMed:7972031, ECO:0000269|PubMed:8071364, CC ECO:0000269|PubMed:8346443, ECO:0000269|PubMed:8367470, CC ECO:0000269|PubMed:8939961}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. The APOE*4 CC allele (APOE form E4) is genetically associated with the common late CC onset familial and sporadic forms of Alzheimer disease. Risk for AD CC increased from 20% to 90% and mean age at onset decreased from 84 to 68 CC years with increasing number of APOE*4 alleles in 42 families with late CC onset AD. Thus APOE*4 gene dose is a major risk factor for late onset CC AD and, in these families, homozygosity for APOE*4 was virtually CC sufficient to cause AD by age 80. The mechanism by which APOE*4 CC participates in pathogenesis is not known. CC {ECO:0000269|PubMed:8346443}. CC -!- DISEASE: Sea-blue histiocyte disease (SBHD) [MIM:269600]: Characterized CC by splenomegaly, mild thrombocytopenia and, in the bone marrow, CC numerous histiocytes containing cytoplasmic granules which stain bright CC blue with the usual hematologic stains. The syndrome is the consequence CC of an inherited metabolic defect analogous to Gaucher disease and other CC sphingolipidoses. {ECO:0000269|PubMed:11095479, CC ECO:0000269|PubMed:16094309, ECO:0000269|PubMed:22481068, CC ECO:0000269|PubMed:22949395, ECO:0000269|PubMed:24267230, CC ECO:0000269|PubMed:26802169}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Lipoprotein glomerulopathy (LPG) [MIM:611771]: Uncommon kidney CC disease characterized by proteinuria, progressive kidney failure, and CC distinctive lipoprotein thrombi in glomerular capillaries. CC {ECO:0000269|PubMed:10432380, ECO:0000269|PubMed:10903326, CC ECO:0000269|PubMed:18077821, ECO:0000269|PubMed:9176854}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- MISCELLANEOUS: Binds to and activates LILRB4 on acute myeloid leukemia CC (AML) cells which leads to suppression of T cell proliferation and CC promotion of AML cell migration and infiltration. CC {ECO:0000269|PubMed:30333625}. CC -!- SIMILARITY: Belongs to the apolipoprotein A1/A4/E family. CC {ECO:0000305}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Apolipoprotein E entry; CC URL="https://en.wikipedia.org/wiki/Apolipoprotein_E"; CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Tangled - Issue 83 of June CC 2007; CC URL="https://www.proteinspotlight.org/back_issues/083"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M12529; AAB59518.1; -; mRNA. DR EMBL; K00396; AAB59546.1; -; mRNA. DR EMBL; M10065; AAB59397.1; -; Genomic_DNA. DR EMBL; AF050154; AAD02505.1; -; Genomic_DNA. DR EMBL; AF261279; AAG27089.1; -; Genomic_DNA. DR EMBL; AK314898; BAG37412.1; -; mRNA. DR EMBL; FJ525876; ACN81314.1; -; Genomic_DNA. DR EMBL; BC003557; AAH03557.1; -; mRNA. DR EMBL; AB035149; BAA96080.1; -; Genomic_DNA. DR CCDS; CCDS12647.1; -. DR PIR; A92478; LPHUE. DR RefSeq; NP_000032.1; NM_000041.4. DR RefSeq; NP_001289617.1; NM_001302688.1. DR RefSeq; NP_001289618.1; NM_001302689.2. DR RefSeq; NP_001289619.1; NM_001302690.2. DR RefSeq; NP_001289620.1; NM_001302691.2. DR PDB; 1B68; X-ray; 2.00 A; A=19-209. DR PDB; 1BZ4; X-ray; 1.85 A; A=40-183. DR PDB; 1EA8; X-ray; 1.95 A; A=19-209. DR PDB; 1GS9; X-ray; 1.70 A; A=19-183. DR PDB; 1H7I; X-ray; 1.90 A; A=19-209. DR PDB; 1LE2; X-ray; 3.00 A; A=41-184. DR PDB; 1LE4; X-ray; 2.50 A; A=41-184. DR PDB; 1LPE; X-ray; 2.25 A; A=41-184. DR PDB; 1NFN; X-ray; 1.80 A; A=19-209. DR PDB; 1NFO; X-ray; 2.00 A; A=19-209. DR PDB; 1OEF; NMR; -; A=281-304. DR PDB; 1OEG; NMR; -; A=285-307. DR PDB; 1OR2; X-ray; 2.50 A; A=19-183. DR PDB; 1OR3; X-ray; 1.73 A; A=19-183. DR PDB; 2KC3; NMR; -; A=19-201. DR PDB; 2KNY; NMR; -; A=147-167. DR PDB; 2L7B; NMR; -; A=19-317. DR PDB; 6IWB; X-ray; 2.50 A; A/C=41-186. DR PDB; 6NCN; X-ray; 1.82 A; A=19-180. DR PDB; 6NCO; X-ray; 1.71 A; A=19-180. DR PDB; 6V7M; X-ray; 2.00 A; A=1-100, B=101-183. DR PDB; 7FCR; X-ray; 1.40 A; A=19-209. DR PDB; 7FCS; X-ray; 1.60 A; A=19-209. DR PDB; 7UVJ; X-ray; 1.99 A; A/B=40-183. DR PDB; 8AX8; X-ray; 1.55 A; A=19-317. DR PDB; 8AX9; X-ray; 1.55 A; A=19-317. DR PDB; 8CDY; X-ray; 1.90 A; A=19-317. DR PDB; 8CE0; X-ray; 1.75 A; A=19-317. DR PDB; 8GRX; EM; 3.00 A; A/C=41-180. DR PDBsum; 1B68; -. DR PDBsum; 1BZ4; -. DR PDBsum; 1EA8; -. DR PDBsum; 1GS9; -. DR PDBsum; 1H7I; -. DR PDBsum; 1LE2; -. DR PDBsum; 1LE4; -. DR PDBsum; 1LPE; -. DR PDBsum; 1NFN; -. DR PDBsum; 1NFO; -. DR PDBsum; 1OEF; -. DR PDBsum; 1OEG; -. DR PDBsum; 1OR2; -. DR PDBsum; 1OR3; -. DR PDBsum; 2KC3; -. DR PDBsum; 2KNY; -. DR PDBsum; 2L7B; -. DR PDBsum; 6IWB; -. DR PDBsum; 6NCN; -. DR PDBsum; 6NCO; -. DR PDBsum; 6V7M; -. DR PDBsum; 7FCR; -. DR PDBsum; 7FCS; -. DR PDBsum; 7UVJ; -. DR PDBsum; 8AX8; -. DR PDBsum; 8AX9; -. DR PDBsum; 8CDY; -. DR PDBsum; 8CE0; -. DR PDBsum; 8GRX; -. DR AlphaFoldDB; P02649; -. DR BMRB; P02649; -. DR EMDB; EMD-34216; -. DR EMDB; EMD-53251; -. DR EMDB; EMD-53269; -. DR EMDB; EMD-53271; -. DR EMDB; EMD-53272; -. DR EMDB; EMD-53273; -. DR EMDB; EMD-53280; -. DR EMDB; EMD-53289; -. DR EMDB; EMD-53292; -. DR EMDB; EMD-53293; -. DR SASBDB; P02649; -. DR SMR; P02649; -. DR BioGRID; 106845; 168. DR CORUM; P02649; -. DR DIP; DIP-1120N; -. DR FunCoup; P02649; 41. DR IntAct; P02649; 102. DR MINT; P02649; -. DR STRING; 9606.ENSP00000252486; -. DR DrugBank; DB09130; Copper. DR DrugBank; DB11886; Infigratinib. DR DrugBank; DB00877; Sirolimus. DR DrugBank; DB00460; Verteporfin. DR DrugBank; DB01593; Zinc. DR DrugBank; DB14487; Zinc acetate. DR DrugBank; DB14533; Zinc chloride. DR DrugBank; DB14548; Zinc sulfate, unspecified form. DR MoonDB; P02649; Predicted. DR TCDB; 9.B.445.2.1; the apolipoprotein a2 (alp-a2) family. DR CarbonylDB; P02649; -. DR GlyConnect; 648; 2 O-Linked glycans (5 sites). DR GlyCosmos; P02649; 8 sites, 5 glycans. DR GlyGen; P02649; 9 sites, 7 O-linked glycans (8 sites). DR iPTMnet; P02649; -. DR MetOSite; P02649; -. DR PhosphoSitePlus; P02649; -. DR SwissPalm; P02649; -. DR BioMuta; APOE; -. DR DMDM; 114039; -. DR CPTAC; non-CPTAC-1087; -. DR jPOST; P02649; -. DR MassIVE; P02649; -. DR PaxDb; 9606-ENSP00000252486; -. DR PeptideAtlas; P02649; -. DR ProteomicsDB; 51537; -. DR Pumba; P02649; -. DR ABCD; P02649; 7 sequenced antibodies. DR Antibodypedia; 3639; 1465 antibodies from 51 providers. DR DNASU; 348; -. DR YCharOS; P02649; Tested 14 antibodies from 8 manufacturers. DR Ensembl; ENST00000252486.9; ENSP00000252486.3; ENSG00000130203.11. DR GeneID; 348; -. DR KEGG; hsa:348; -. DR MANE-Select; ENST00000252486.9; ENSP00000252486.3; NM_000041.4; NP_000032.1. DR UCSC; uc002pab.4; human. DR AGR; HGNC:613; -. DR ClinPGx; PA55; -. DR CTD; 348; -. DR DisGeNET; 348; -. DR GeneCards; APOE; -. DR HGNC; HGNC:613; APOE. DR HPA; ENSG00000130203; Group enriched (adrenal gland, brain, liver). DR MalaCards; APOE; -. DR MIM; 104310; phenotype. DR MIM; 107741; gene. DR MIM; 269600; phenotype. DR MIM; 611771; phenotype. DR MIM; 617347; phenotype. DR OpenTargets; ENSG00000130203; -. DR Orphanet; 412; Dysbetalipoproteinemia. DR Orphanet; 329481; Lipoprotein glomerulopathy. DR VEuPathDB; HostDB:ENSG00000130203; -. DR eggNOG; ENOG502QVD6; Eukaryota. DR GeneTree; ENSGT00950000182929; -. DR HOGENOM; CLU_066029_0_0_1; -. DR InParanoid; P02649; -. DR OMA; GHMTDAR; -. DR OrthoDB; 9048614at2759; -. DR PAN-GO; P02649; 9 GO annotations based on evolutionary models. DR PhylomeDB; P02649; -. DR PathwayCommons; P02649; -. DR Reactome; R-HSA-1251985; Nuclear signaling by ERBB4. DR Reactome; R-HSA-3000480; Scavenging by Class A Receptors. DR Reactome; R-HSA-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs). DR Reactome; R-HSA-8864260; Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors. DR Reactome; R-HSA-8957275; Post-translational protein phosphorylation. DR Reactome; R-HSA-8963888; Chylomicron assembly. DR Reactome; R-HSA-8963901; Chylomicron remodeling. DR Reactome; R-HSA-8964026; Chylomicron clearance. DR Reactome; R-HSA-8964058; HDL remodeling. DR Reactome; R-HSA-9029569; NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux. DR Reactome; R-HSA-975634; Retinoid metabolism and transport. DR Reactome; R-HSA-977225; Amyloid fiber formation. DR SignaLink; P02649; -. DR SIGNOR; P02649; -. DR Agora; ENSG00000130203; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 348; 20 hits in 1163 CRISPR screens. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; APOE; human. DR EvolutionaryTrace; P02649; -. DR GeneWiki; Apolipoprotein_E; -. DR GenomeRNAi; 348; -. DR Pharos; P02649; Tbio. DR PRO; PR:P02649; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; P02649; protein. DR Bgee; ENSG00000130203; Expressed in right adrenal gland cortex and 179 other cell types or tissues. DR ExpressionAtlas; P02649; baseline and differential. DR GO; GO:0072562; C:blood microparticle; HDA:UniProtKB. DR GO; GO:0042627; C:chylomicron; IDA:BHF-UCL. DR GO; GO:0034360; C:chylomicron remnant; IDA:ARUK-UCL. DR GO; GO:0030669; C:clathrin-coated endocytic vesicle membrane; TAS:Reactome. DR GO; GO:0005737; C:cytoplasm; TAS:UniProtKB. DR GO; GO:0030425; C:dendrite; NAS:BHF-UCL. DR GO; GO:0034365; C:discoidal high-density lipoprotein particle; TAS:ARUK-UCL. DR GO; GO:0005769; C:early endosome; TAS:Reactome. DR GO; GO:0071682; C:endocytic vesicle lumen; TAS:Reactome. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:AgBase. DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome. DR GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB. DR GO; GO:0031012; C:extracellular matrix; IDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; IDA:ARUK-UCL. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:1903561; C:extracellular vesicle; HDA:UniProtKB. DR GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO. DR GO; GO:0005794; C:Golgi apparatus; IDA:AgBase. DR GO; GO:0034364; C:high-density lipoprotein particle; IDA:UniProtKB. DR GO; GO:0034363; C:intermediate-density lipoprotein particle; IDA:UniProtKB. DR GO; GO:1990777; C:lipoprotein particle; IDA:ARUK-UCL. DR GO; GO:0034362; C:low-density lipoprotein particle; IDA:UniProtKB. DR GO; GO:0042470; C:melanosome; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0097487; C:multivesicular body, internal vesicle; IDA:UniProtKB. DR GO; GO:0043025; C:neuronal cell body; NAS:BHF-UCL. DR GO; GO:0005634; C:nucleus; HDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0043083; C:synaptic cleft; IDA:SynGO. DR GO; GO:0034361; C:very-low-density lipoprotein particle; IDA:UniProtKB. DR GO; GO:0001540; F:amyloid-beta binding; IDA:UniProtKB. DR GO; GO:0016209; F:antioxidant activity; IDA:BHF-UCL. DR GO; GO:0120020; F:cholesterol transfer activity; IBA:GO_Central. DR GO; GO:0019899; F:enzyme binding; IPI:BHF-UCL. DR GO; GO:0043395; F:heparan sulfate proteoglycan binding; IDA:UniProtKB. DR GO; GO:0008201; F:heparin binding; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IDA:UniProtKB. DR GO; GO:0008289; F:lipid binding; IDA:UniProtKB. DR GO; GO:0005319; F:lipid transporter activity; IDA:BHF-UCL. DR GO; GO:0071813; F:lipoprotein particle binding; IEA:Ensembl. DR GO; GO:0050750; F:low-density lipoprotein particle receptor binding; IDA:UniProtKB. DR GO; GO:0046911; F:metal chelating activity; IDA:BHF-UCL. DR GO; GO:0060228; F:phosphatidylcholine-sterol O-acyltransferase activator activity; IDA:BHF-UCL. DR GO; GO:0005543; F:phospholipid binding; IDA:BHF-UCL. DR GO; GO:0046983; F:protein dimerization activity; IPI:ARUK-UCL. DR GO; GO:0042803; F:protein homodimerization activity; IPI:ARUK-UCL. DR GO; GO:0044877; F:protein-containing complex binding; IDA:ARUK-UCL. DR GO; GO:0048018; F:receptor ligand activity; IDA:UniProt. DR GO; GO:0005102; F:signaling receptor binding; IPI:ARUK-UCL. DR GO; GO:0005198; F:structural molecule activity; TAS:ARUK-UCL. DR GO; GO:0048156; F:tau protein binding; IPI:BHF-UCL. DR GO; GO:0070326; F:very-low-density lipoprotein particle receptor binding; IDA:BHF-UCL. DR GO; GO:0055090; P:acylglycerol homeostasis; IBA:GO_Central. DR GO; GO:0097113; P:AMPA glutamate receptor clustering; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0042982; P:amyloid precursor protein metabolic process; IDA:UniProtKB. DR GO; GO:0048844; P:artery morphogenesis; IEA:Ensembl. DR GO; GO:0071402; P:cellular response to lipoprotein particle stimulus; IDA:UniProt. DR GO; GO:0006707; P:cholesterol catabolic process; IEA:Ensembl. DR GO; GO:0033344; P:cholesterol efflux; IDA:UniProtKB. DR GO; GO:0042632; P:cholesterol homeostasis; IDA:BHF-UCL. DR GO; GO:0008203; P:cholesterol metabolic process; IDA:BHF-UCL. DR GO; GO:0034382; P:chylomicron remnant clearance; IDA:UniProtKB. DR GO; GO:0007010; P:cytoskeleton organization; TAS:UniProtKB. DR GO; GO:0055089; P:fatty acid homeostasis; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0010467; P:gene expression; IEA:Ensembl. DR GO; GO:0034380; P:high-density lipoprotein particle assembly; IDA:UniProtKB. DR GO; GO:0034384; P:high-density lipoprotein particle clearance; IDA:BHF-UCL. DR GO; GO:0034375; P:high-density lipoprotein particle remodeling; IGI:BHF-UCL. DR GO; GO:0044794; P:host-mediated activation of viral process; IMP:AgBase. DR GO; GO:0071831; P:intermediate-density lipoprotein particle clearance; IDA:UniProtKB. DR GO; GO:0006874; P:intracellular calcium ion homeostasis; IEA:Ensembl. DR GO; GO:0046907; P:intracellular transport; TAS:UniProtKB. DR GO; GO:0010877; P:lipid transport involved in lipid storage; ISS:BHF-UCL. DR GO; GO:0042158; P:lipoprotein biosynthetic process; IDA:UniProtKB. DR GO; GO:0042159; P:lipoprotein catabolic process; IEA:Ensembl. DR GO; GO:0035641; P:locomotory exploration behavior; IMP:ARUK-UCL. DR GO; GO:0015909; P:long-chain fatty acid transport; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0007616; P:long-term memory; IGI:ARUK-UCL. DR GO; GO:0034374; P:low-density lipoprotein particle remodeling; IEA:Ensembl. DR GO; GO:0051651; P:maintenance of location in cell; IEA:Ensembl. DR GO; GO:0032438; P:melanosome organization; IMP:UniProtKB. DR GO; GO:1905907; P:negative regulation of amyloid fibril formation; ISS:UniProtKB. DR GO; GO:1902430; P:negative regulation of amyloid-beta formation; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0030195; P:negative regulation of blood coagulation; IDA:BHF-UCL. DR GO; GO:0043537; P:negative regulation of blood vessel endothelial cell migration; IDA:BHF-UCL. DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IDA:ARUK-UCL. DR GO; GO:0045541; P:negative regulation of cholesterol biosynthetic process; IDA:BHF-UCL. DR GO; GO:0010596; P:negative regulation of endothelial cell migration; IMP:ARUK-UCL. DR GO; GO:0001937; P:negative regulation of endothelial cell proliferation; IDA:BHF-UCL. DR GO; GO:0010629; P:negative regulation of gene expression; ISS:ARUK-UCL. DR GO; GO:0050728; P:negative regulation of inflammatory response; IDA:BHF-UCL. DR GO; GO:1900272; P:negative regulation of long-term synaptic potentiation; IDA:ARUK-UCL. DR GO; GO:0043409; P:negative regulation of MAPK cascade; IDA:BHF-UCL. DR GO; GO:0010977; P:negative regulation of neuron projection development; IDA:ARUK-UCL. DR GO; GO:0010544; P:negative regulation of platelet activation; IDA:BHF-UCL. DR GO; GO:0010642; P:negative regulation of platelet-derived growth factor receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0051248; P:negative regulation of protein metabolic process; IGI:ARUK-UCL. DR GO; GO:0050709; P:negative regulation of protein secretion; IMP:UniProtKB. DR GO; GO:0048662; P:negative regulation of smooth muscle cell proliferation; ISS:BHF-UCL. DR GO; GO:0090209; P:negative regulation of triglyceride metabolic process; IEA:Ensembl. DR GO; GO:0031175; P:neuron projection development; IDA:UniProtKB. DR GO; GO:0038060; P:nitric oxide-cGMP-mediated signaling; IDA:BHF-UCL. DR GO; GO:0097114; P:NMDA glutamate receptor clustering; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0033700; P:phospholipid efflux; IDA:BHF-UCL. DR GO; GO:1905908; P:positive regulation of amyloid fibril formation; TAS:ARUK-UCL. DR GO; GO:1900223; P:positive regulation of amyloid-beta clearance; ISS:UniProtKB. DR GO; GO:0010875; P:positive regulation of cholesterol efflux; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0090205; P:positive regulation of cholesterol metabolic process; IDA:BHF-UCL. DR GO; GO:0060999; P:positive regulation of dendritic spine development; IDA:Alzheimers_University_of_Toronto. DR GO; GO:1902952; P:positive regulation of dendritic spine maintenance; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IMP:UniProtKB. DR GO; GO:0045807; P:positive regulation of endocytosis; IDA:ARUK-UCL. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:UniProtKB. DR GO; GO:0046889; P:positive regulation of lipid biosynthetic process; IDA:Alzheimers_University_of_Toronto. DR GO; GO:1903002; P:positive regulation of lipid transport across blood-brain barrier; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0140077; P:positive regulation of lipoprotein transport; IDA:ARUK-UCL. DR GO; GO:0032805; P:positive regulation of low-density lipoprotein particle receptor catabolic process; IDA:BHF-UCL. DR GO; GO:0051044; P:positive regulation of membrane protein ectodomain proteolysis; IDA:BHF-UCL. DR GO; GO:0010976; P:positive regulation of neuron projection development; IDA:ARUK-UCL. DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IDA:BHF-UCL. DR GO; GO:1902995; P:positive regulation of phospholipid efflux; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0017038; P:protein import; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0006898; P:receptor-mediated endocytosis; IDA:BHF-UCL. DR GO; GO:1905906; P:regulation of amyloid fibril formation; IDA:ARUK-UCL. DR GO; GO:1902991; P:regulation of amyloid precursor protein catabolic process; IDA:UniProtKB. DR GO; GO:1900221; P:regulation of amyloid-beta clearance; IDA:Alzheimers_University_of_Toronto. DR GO; GO:0042981; P:regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0030516; P:regulation of axon extension; TAS:UniProtKB. DR GO; GO:2000822; P:regulation of behavioral fear response; IMP:ARUK-UCL. DR GO; GO:0032489; P:regulation of Cdc42 protein signal transduction; IDA:BHF-UCL. DR GO; GO:1905890; P:regulation of cellular response to very-low-density lipoprotein particle stimulus; IDA:ARUK-UCL. DR GO; GO:0090181; P:regulation of cholesterol metabolic process; IGI:ARUK-UCL. DR GO; GO:0045088; P:regulation of innate immune response; IEA:Ensembl. DR GO; GO:0048168; P:regulation of neuronal synaptic plasticity; TAS:UniProtKB. DR GO; GO:0061136; P:regulation of proteasomal protein catabolic process; IMP:UniProtKB. DR GO; GO:0051246; P:regulation of protein metabolic process; IGI:ARUK-UCL. DR GO; GO:0043254; P:regulation of protein-containing complex assembly; IDA:ARUK-UCL. DR GO; GO:0061771; P:response to caloric restriction; IGI:ARUK-UCL. DR GO; GO:0002021; P:response to dietary excess; IEA:Ensembl. DR GO; GO:0000302; P:response to reactive oxygen species; NAS:UniProtKB. DR GO; GO:0043691; P:reverse cholesterol transport; IDA:BHF-UCL. DR GO; GO:0007271; P:synaptic transmission, cholinergic; TAS:UniProtKB. DR GO; GO:0070328; P:triglyceride homeostasis; ISS:BHF-UCL. DR GO; GO:0006641; P:triglyceride metabolic process; IDA:BHF-UCL. DR GO; GO:0071830; P:triglyceride-rich lipoprotein particle clearance; IMP:UniProtKB. DR GO; GO:0042311; P:vasodilation; IEA:Ensembl. DR GO; GO:0034447; P:very-low-density lipoprotein particle clearance; IDA:UniProtKB. DR GO; GO:0034372; P:very-low-density lipoprotein particle remodeling; IDA:BHF-UCL. DR GO; GO:0019068; P:virion assembly; IMP:AgBase. DR DisProt; DP04133; -. DR FunFam; 1.20.120.20:FF:000002; Apolipoprotein E; 1. DR FunFam; 1.20.120.20:FF:000003; Apolipoprotein E; 1. DR Gene3D; 1.20.120.20; Apolipoprotein; 2. DR InterPro; IPR000074; ApoA_E. DR InterPro; IPR050163; Apolipoprotein_A1/A4/E. DR PANTHER; PTHR18976; APOLIPOPROTEIN; 1. DR PANTHER; PTHR18976:SF2; APOLIPOPROTEIN E; 1. DR Pfam; PF01442; Apolipoprotein; 1. DR SUPFAM; SSF58113; Apolipoprotein A-I; 1. PE 1: Evidence at protein level; KW 3D-structure; Alzheimer disease; Amyloidosis; Cholesterol metabolism; KW Chylomicron; Direct protein sequencing; Disease variant; Endosome; KW Extracellular matrix; Glycation; Glycoprotein; HDL; Heparin-binding; KW Host-virus interaction; Hyperlipidemia; Lipid metabolism; Lipid transport; KW Lipid-binding; Neurodegeneration; Oxidation; Phosphoprotein; KW Proteomics identification; Reference proteome; Repeat; Secreted; Signal; KW Steroid metabolism; Sterol metabolism; Transport; VLDL. FT SIGNAL 1..18 FT /evidence="ECO:0000269|PubMed:7068630" FT CHAIN 19..317 FT /note="Apolipoprotein E" FT /id="PRO_0000001987" FT REPEAT 80..101 FT /note="1" FT REPEAT 102..123 FT /note="2" FT REPEAT 124..145 FT /note="3" FT REPEAT 146..167 FT /note="4" FT REPEAT 168..189 FT /note="5" FT REPEAT 190..211 FT /note="6" FT REPEAT 212..233 FT /note="7" FT REPEAT 234..255 FT /note="8" FT REGION 80..255 FT /note="8 X 22 AA approximate tandem repeats" FT REGION 158..168 FT /note="LDL and other lipoprotein receptors binding" FT /evidence="ECO:0000269|PubMed:20030366, FT ECO:0000269|PubMed:2063194" FT REGION 210..290 FT /note="Lipid-binding and lipoprotein association" FT /evidence="ECO:0000269|PubMed:2280190, FT ECO:0000269|PubMed:8071364" FT REGION 266..317 FT /note="Homooligomerization" FT /evidence="ECO:0000269|PubMed:8340399" FT REGION 278..290 FT /note="Specificity for association with VLDL" FT /evidence="ECO:0000269|PubMed:8071364" FT BINDING 162..165 FT /ligand="heparin" FT /ligand_id="ChEBI:CHEBI:28304" FT /evidence="ECO:0000269|PubMed:3947350" FT BINDING 229..236 FT /ligand="heparin" FT /ligand_id="ChEBI:CHEBI:28304" FT /evidence="ECO:0000269|PubMed:3947350" FT MOD_RES 143 FT /note="Methionine sulfoxide" FT /evidence="ECO:0000250|UniProtKB:P08226" FT MOD_RES 147 FT /note="Phosphoserine; by FAM20C" FT /evidence="ECO:0000269|PubMed:26091039, FT ECO:0007744|PubMed:24275569" FT CARBOHYD 26 FT /note="O-linked (GalNAc...) threonine" FT /evidence="ECO:0000269|PubMed:23234360" FT CARBOHYD 36 FT /note="O-linked (GalNAc...) threonine" FT /evidence="ECO:0000269|PubMed:23234360" FT CARBOHYD 93 FT /note="N-linked (Glc) (glycation) lysine" FT /evidence="ECO:0000269|PubMed:10452964" FT CARBOHYD 212 FT /note="O-linked (GalNAc...) threonine" FT /evidence="ECO:0000269|PubMed:19838169, FT ECO:0000269|PubMed:2498325" FT CARBOHYD 307 FT /note="O-linked (GalNAc...) threonine" FT /evidence="ECO:0000269|PubMed:19838169" FT CARBOHYD 308 FT /note="O-linked (GalNAc...) serine" FT /evidence="ECO:0000269|PubMed:19838169, FT ECO:0000269|PubMed:20511397" FT CARBOHYD 314 FT /note="O-linked (GalNAc...) serine" FT /evidence="ECO:0000269|PubMed:23234360" FT VARIANT 21 FT /note="E -> K (in ApoE5; associated with FT hyperlipoproteinemia and atherosclerosis; increased binding FT to LDL receptor; dbSNP:rs121918392)" FT /evidence="ECO:0000269|PubMed:1530612, FT ECO:0000269|PubMed:2760009" FT /id="VAR_000645" FT VARIANT 31 FT /note="E -> K (in HLPP3; ApoE4 Philadelphia, ApoE5 French- FT Canadian and ApoE5-type; only ApoE4 Philadelphia is FT associated with HLPP3; dbSNP:rs201672011)" FT /evidence="ECO:0000269|PubMed:1674745, FT ECO:0000269|PubMed:1713245, ECO:0000303|PubMed:7833947" FT /id="VAR_000646" FT VARIANT 43 FT /note="R -> C (in LPG; ApoE2 Kyoto; dbSNP:rs121918399)" FT /evidence="ECO:0000269|PubMed:10432380, FT ECO:0000269|PubMed:18077821" FT /id="VAR_042734" FT VARIANT 46 FT /note="L -> P (found in a patient with FT hypercholesterolemia; uncertain significance; ApoE4 FT Freiburg; dbSNP:rs769452)" FT /evidence="ECO:0000269|PubMed:11042151, FT ECO:0000269|PubMed:26802169" FT /id="VAR_000647" FT VARIANT 60 FT /note="T -> A (in ApoE3 Freiburg; dbSNP:rs28931576)" FT /id="VAR_000648" FT VARIANT 64 FT /note="Q -> H (confirmed at protein level; FT dbSNP:rs370594287)" FT /evidence="ECO:0000269|PubMed:22028381, ECO:0000269|Ref.10" FT /id="VAR_014114" FT VARIANT 99 FT /note="Q -> K (in ApoE5 Frankfurt; dbSNP:rs1180612218)" FT /evidence="ECO:0000269|PubMed:8125051" FT /id="VAR_000649" FT VARIANT 102 FT /note="P -> R (apoE5-type; no hyperlipidemia; FT dbSNP:rs11083750)" FT /evidence="ECO:0000269|PubMed:7833947" FT /id="VAR_000650" FT VARIANT 117 FT /note="A -> T (in ApoE3*; dbSNP:rs28931577)" FT /evidence="ECO:0000269|PubMed:6327682" FT /id="VAR_000651" FT VARIANT 124 FT /note="A -> V (in ApoE3 Basel; dbSNP:rs937063425)" FT /evidence="ECO:0000269|PubMed:12864777" FT /id="VAR_016789" FT VARIANT 130 FT /note="C -> R (in HLPP3 and AD2; ApoE4, ApoE3 Leiden, FT ApoE3**, ApoE5-Frankfurt and ApoE5-type; ApoE3 Leiden and FT ApoE3** are associated with HLPP3; ApoE4 is associated with FT AD2; changed protein structure; no effect on binding to LDL FT receptor; decreased association with HDL and enrichment in FT VLDL and IDL; may prevent the interaction with MAP2 and FT MAPT; changed interaction with APP/A4 amyloid-beta peptide; FT increased ability to induce APP transcription; increased C- FT terminal proteolytic processing in neurons; decreased FT function in neurite outgrowth; ApoE4 is associated with FT higher susceptibility to SARS-CoV-2 infection in neurons FT and astrocytes; dbSNP:rs429358)" FT /evidence="ECO:0000269|PubMed:10903326, FT ECO:0000269|PubMed:11042151, ECO:0000269|PubMed:11447277, FT ECO:0000269|PubMed:12966036, ECO:0000269|PubMed:2280190, FT ECO:0000269|PubMed:2556398, ECO:0000269|PubMed:28111074, FT ECO:0000269|PubMed:2987927, ECO:0000269|PubMed:7891887, FT ECO:0000269|PubMed:7972031, ECO:0000269|PubMed:8071364, FT ECO:0000269|PubMed:8125051, ECO:0000269|PubMed:8287539, FT ECO:0000269|PubMed:8346443, ECO:0000269|PubMed:8367470, FT ECO:0000269|PubMed:8939961, ECO:0000269|PubMed:9360638, FT ECO:0000303|PubMed:7833947" FT /id="VAR_000652" FT VARIANT 145 FT /note="G -> D (found in a patient with FT hypercholesterolemia; uncertain significance; ApoE1 FT Weisgraber; dbSNP:rs267606664)" FT /evidence="ECO:0000269|PubMed:26802169, FT ECO:0000269|PubMed:8287539" FT /id="VAR_000653" FT VARIANT 145 FT /note="G -> GEVQAMLG (in HLPP3; ApoE3 Leiden; no effect on FT glycosylation)" FT /evidence="ECO:0000269|PubMed:2556398, FT ECO:0000269|PubMed:8468528" FT /id="VAR_000654" FT VARIANT 152 FT /note="R -> Q (apoE2-type; no hyperlipidemia; FT dbSNP:rs28931578)" FT /evidence="ECO:0000269|PubMed:7833947" FT /id="VAR_000655" FT VARIANT 154 FT /note="R -> C (in HLPP3; ApoE2-type; dbSNP:rs121918393)" FT /evidence="ECO:0000303|PubMed:7833947" FT /id="VAR_000657" FT VARIANT 154 FT /note="R -> S (in HLPP3; ApoE2 Christchurch; decreased FT binding to LDL receptor; dbSNP:rs121918393)" FT /evidence="ECO:0000269|PubMed:22481068, FT ECO:0000269|PubMed:2831187, ECO:0000269|PubMed:8287539" FT /id="VAR_000656" FT VARIANT 160 FT /note="R -> C (in HLPP3; ApoE3**; dbSNP:rs387906567)" FT /evidence="ECO:0000269|PubMed:8287539" FT /id="VAR_000658" FT VARIANT 163 FT /note="R -> C (in HLPP3; also found in a patient with FT hypercholesterolemia; ApoE4 Philadelphia and ApoE2-type; FT dbSNP:rs769455)" FT /evidence="ECO:0000269|PubMed:11042151, FT ECO:0000269|PubMed:1674745, ECO:0000269|PubMed:26802169" FT /id="VAR_000659" FT VARIANT 163 FT /note="R -> H (in HLPP3; uncertain significance; ApoE FT Kochi; dbSNP:rs121918397)" FT /evidence="ECO:0000269|PubMed:2101409" FT /id="VAR_000660" FT VARIANT 163 FT /note="R -> P (in LPG; ApoE2 Sendai; decreased binding to FT LDL receptor; induces intraglomerular deposition of ApoE- FT containing lipoproteins; dbSNP:rs121918397)" FT /evidence="ECO:0000269|PubMed:10903326, FT ECO:0000269|PubMed:9176854" FT /id="VAR_042735" FT VARIANT 164 FT /note="K -> E (in HLPP3; ApoE1 Harrisburg; decreased FT binding to LDL receptor; probable dominant negative effect; FT decreased in vitro binding to heparin; dbSNP:rs121918394)" FT /evidence="ECO:0000269|PubMed:7635945" FT /id="VAR_000662" FT VARIANT 164 FT /note="K -> Q (in HLPP3; ApoE2**; dbSNP:rs121918394)" FT /evidence="ECO:0000269|PubMed:2313204" FT /id="VAR_000661" FT VARIANT 167 FT /note="Missing (in SBHD; also found in patients with a FT diagnosis of familial combined hyperlipidemia)" FT /evidence="ECO:0000269|PubMed:11095479, FT ECO:0000269|PubMed:16094309, ECO:0000269|PubMed:22481068, FT ECO:0000269|PubMed:22949395, ECO:0000269|PubMed:24267230, FT ECO:0000269|PubMed:26802169" FT /id="VAR_035015" FT VARIANT 170 FT /note="A -> P (in ApoE3*; decreased binding to LDL FT receptor; dbSNP:rs267606662)" FT /evidence="ECO:0000269|PubMed:2831187, FT ECO:0000269|PubMed:6327682" FT /id="VAR_000663" FT VARIANT 176 FT /note="R -> C (in HLPP3; ApoE2, ApoE2 Fukuoka, ApoE1 FT Weisgraber and ApoE3**; ApoE3** is associated with HLPP3; FT changed protein structure; decreased binding to LDLR and FT other lipoprotein receptors; decreased in vitro binding to FT heparin; no effect on distribution among plasma FT lipoproteins; dbSNP:rs7412)" FT /evidence="ECO:0000269|PubMed:11042151, FT ECO:0000269|PubMed:12950167, ECO:0000269|PubMed:12966036, FT ECO:0000269|PubMed:2280190, ECO:0000269|PubMed:3243553, FT ECO:0000269|PubMed:7635945, ECO:0000269|PubMed:7994571, FT ECO:0000269|PubMed:8287539, ECO:0000269|PubMed:8756331" FT /id="VAR_000664" FT VARIANT 228..317 FT /note="Missing (in HLPP3; ApoE3 Washington)" FT /evidence="ECO:0000269|PubMed:1361196" FT /id="VAR_081136" FT VARIANT 242 FT /note="R -> Q (in ApoE2 Fukuoka; dbSNP:rs267606663)" FT /evidence="ECO:0000269|PubMed:8664327" FT /id="VAR_000665" FT VARIANT 246 FT /note="R -> C (in ApoE2 Dunedin; dbSNP:rs121918395)" FT /evidence="ECO:0000269|PubMed:2341812" FT /id="VAR_000666" FT VARIANT 254 FT /note="V -> E (in ApoE2 WG; dbSNP:rs199768005)" FT /evidence="ECO:0000269|PubMed:8488843" FT /id="VAR_000667" FT VARIANT 262..263 FT /note="EE -> KK (in HLPP3; ApoE7 Suita)" FT /evidence="ECO:0000269|PubMed:2738044" FT /id="VAR_000668" FT VARIANT 269 FT /note="R -> G (in ApoE3 HB; dbSNP:rs267606661)" FT /evidence="ECO:0000269|PubMed:8488843, FT ECO:0000269|PubMed:9360638" FT /id="VAR_000669" FT VARIANT 270 FT /note="L -> E (in ApoE1 HE; requires 2 nucleotide FT substitutions)" FT /evidence="ECO:0000269|PubMed:8488843" FT /id="VAR_000670" FT VARIANT 292 FT /note="R -> H (in ApoE4 PD; dbSNP:rs121918398)" FT /evidence="ECO:0000269|PubMed:8488843" FT /id="VAR_000671" FT VARIANT 314 FT /note="S -> R (in ApoE4 HG; dbSNP:rs28931579)" FT /evidence="ECO:0000269|PubMed:8488843" FT /id="VAR_000672" FT MUTAGEN 79 FT /note="R->T: Changes the plasma lipoprotein distribution of FT ApoE4 to the HDL." FT /evidence="ECO:0000269|PubMed:8071364" FT MUTAGEN 127 FT /note="E->A: No effect on plasma lipoprotein distribution." FT /evidence="ECO:0000269|PubMed:8071364" FT MUTAGEN 157 FT /note="S->R: Increased binding to LDL receptor; when FT associated with A-167." FT /evidence="ECO:0000269|PubMed:2831187" FT MUTAGEN 158 FT /note="H->A: Decreased binding to LDL receptor." FT /evidence="ECO:0000269|PubMed:2831187" FT MUTAGEN 161 FT /note="K->A: Decreased binding to LDL receptor." FT /evidence="ECO:0000269|PubMed:2831187" FT MUTAGEN 162 FT /note="L->P: Decreased binding to LDL receptor." FT /evidence="ECO:0000269|PubMed:2831187" FT MUTAGEN 167 FT /note="L->A: Increased binding to LDL receptor; when FT associated with R-157." FT /evidence="ECO:0000269|PubMed:2831187" FT MUTAGEN 168 FT /note="R->A: Decreased binding to LDL receptor." FT /evidence="ECO:0000269|PubMed:2831187" FT MUTAGEN 172 FT /note="D->A: Restores the LDL receptor binding activity of FT ApoE2." FT /evidence="ECO:0000269|PubMed:8756331" FT MUTAGEN 212 FT /note="T->A: Loss of O-glycosylation." FT /evidence="ECO:0000269|PubMed:2498325" FT STRAND 22..24 FT /evidence="ECO:0007829|PDB:2KC3" FT HELIX 31..39 FT /evidence="ECO:0007829|PDB:2KC3" FT TURN 40..42 FT /evidence="ECO:0007829|PDB:2KC3" FT HELIX 43..60 FT /evidence="ECO:0007829|PDB:7FCR" FT HELIX 63..70 FT /evidence="ECO:0007829|PDB:7FCR" FT HELIX 73..96 FT /evidence="ECO:0007829|PDB:7FCR" FT HELIX 97..99 FT /evidence="ECO:0007829|PDB:7FCR" FT STRAND 103..105 FT /evidence="ECO:0007829|PDB:7UVJ" FT HELIX 107..142 FT /evidence="ECO:0007829|PDB:7FCR" FT TURN 143..145 FT /evidence="ECO:0007829|PDB:7FCR" FT HELIX 149..180 FT /evidence="ECO:0007829|PDB:7FCR" FT TURN 187..190 FT /evidence="ECO:0007829|PDB:2KC3" FT HELIX 193..198 FT /evidence="ECO:0007829|PDB:2KC3" FT STRAND 200..202 FT /evidence="ECO:0007829|PDB:2L7B" FT HELIX 209..217 FT /evidence="ECO:0007829|PDB:2L7B" FT HELIX 228..241 FT /evidence="ECO:0007829|PDB:2L7B" FT HELIX 257..283 FT /evidence="ECO:0007829|PDB:2L7B" FT HELIX 286..303 FT /evidence="ECO:0007829|PDB:1OEF" FT STRAND 307..309 FT /evidence="ECO:0007829|PDB:2L7B" SQ SEQUENCE 317 AA; 36154 MW; 91AFC04210A30689 CRC64; MKVLWAALLV TFLAGCQAKV EQAVETEPEP ELRQQTEWQS GQRWELALGR FWDYLRWVQT LSEQVQEELL SSQVTQELRA LMDETMKELK AYKSELEEQL TPVAEETRAR LSKELQAAQA RLGADMEDVC GRLVQYRGEV QAMLGQSTEE LRVRLASHLR KLRKRLLRDA DDLQKRLAVY QAGAREGAER GLSAIRERLG PLVEQGRVRA ATVGSLAGQP LQERAQAWGE RLRARMEEMG SRTRDRLDEV KEQVAEVRAK LEEQAQQIRL QAEAFQARLK SWFEPLVEDM QRQWAGLVEK VQAAVGTSAA PVPSDNH // ID ASA2B_HUMAN Reviewed; 165 AA. AC P0C7U1; B7Z261; DT 22-JUL-2008, integrated into UniProtKB/Swiss-Prot. DT 22-JUL-2008, sequence version 1. DT 28-JAN-2026, entry version 110. DE RecName: Full=Putative inactive neutral ceramidase B {ECO:0000305}; DE AltName: Full=ASAH2-like protein {ECO:0000305}; DE AltName: Full=Putative inactive N-acylsphingosine amidohydrolase 2B {ECO:0000305}; DE AltName: Full=Putative inactive non-lysosomal ceramidase B {ECO:0000305}; GN Name=ASAH2B {ECO:0000312|HGNC:HGNC:23456}; GN Synonyms=ASAH2C {ECO:0000312|HGNC:HGNC:23456}, GN ASAH2L {ECO:0000312|HGNC:HGNC:23456}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Amygdala; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164054; DOI=10.1038/nature02462; RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P., RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 10."; RL Nature 429:375-381(2004). RN [3] RP TISSUE SPECIFICITY. RX PubMed=17334805; DOI=10.1007/s10048-007-0081-5; RA Avramopoulos D., Wang R., Valle D., Fallin M.D., Bassett S.S.; RT "A novel gene derived from a segmental duplication shows perturbed RT expression in Alzheimer's disease."; RL Neurogenetics 8:111-120(2007). CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P0C7U1-1; Sequence=Displayed; CC Name=2; CC IsoId=P0C7U1-2; Sequence=VSP_056938; CC -!- TISSUE SPECIFICITY: Ubiquitous. Expression is reduced with increasing CC age and in late-onset Alzheimer disease (LOAD) patients. This reduction CC is even more pronounced in patients with an affected mother. CC {ECO:0000269|PubMed:17334805}. CC -!- MISCELLANEOUS: ASAH2B/ASAH2L is a partial paralog of ASAH2, resulting CC from a partial duplication of ASAH2 on chromosome 10. It has a CC polymorphic start codon with a single nucleotide change of the original CC ASAH2 sequence plus other putative translation start site that might CC lead to several potential ORFs. CC -!- SIMILARITY: Belongs to the neutral ceramidase family. {ECO:0000305}. CC -!- CAUTION: In contrast to other members of the family, ASAH2B has no CC predicted transmembrane domain, and lacks the active site, suggesting CC that it may be catalytically inactive. {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; AK294369; BAH11747.1; -; mRNA. DR EMBL; AL589794; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR CCDS; CCDS31203.1; -. [P0C7U1-1] DR CCDS; CCDS81465.1; -. [P0C7U1-2] DR RefSeq; NP_001072984.1; NM_001079516.4. [P0C7U1-1] DR RefSeq; NP_001308886.1; NM_001321957.2. [P0C7U1-1] DR RefSeq; NP_001308887.1; NM_001321958.2. [P0C7U1-2] DR RefSeq; NP_001308888.1; NM_001321959.2. [P0C7U1-2] DR RefSeq; NP_001308889.1; NM_001321960.2. [P0C7U1-2] DR AlphaFoldDB; P0C7U1; -. DR SMR; P0C7U1; -. DR BioGRID; 575684; 1. DR STRING; 9606.ENSP00000495463; -. DR iPTMnet; P0C7U1; -. DR PhosphoSitePlus; P0C7U1; -. DR BioMuta; ASAH2B; -. DR MassIVE; P0C7U1; -. DR PaxDb; 9606-ENSP00000363118; -. DR PeptideAtlas; P0C7U1; -. DR ProteomicsDB; 52369; -. [P0C7U1-1] DR ProteomicsDB; 6411; -. DR Antibodypedia; 62326; 1 antibodies from 1 providers. DR DNASU; 653308; -. DR Ensembl; ENST00000374006.1; ENSP00000363118.1; ENSG00000204147.12. [P0C7U1-1] DR Ensembl; ENST00000374007.5; ENSP00000363119.1; ENSG00000204147.12. [P0C7U1-2] DR Ensembl; ENST00000643851.1; ENSP00000495463.1; ENSG00000204147.12. [P0C7U1-1] DR Ensembl; ENST00000647317.2; ENSP00000496089.1; ENSG00000204147.12. [P0C7U1-2] DR GeneID; 653308; -. DR KEGG; hsa:653308; -. DR MANE-Select; ENST00000647317.2; ENSP00000496089.1; NM_001321958.2; NP_001308887.1. [P0C7U1-2] DR UCSC; uc001jjg.5; human. [P0C7U1-1] DR AGR; HGNC:23456; -. DR ClinPGx; PA134977109; -. DR CTD; 653308; -. DR DisGeNET; 653308; -. DR GeneCards; ASAH2B; -. DR HGNC; HGNC:23456; ASAH2B. DR HPA; ENSG00000204147; Tissue enhanced (intestine). DR MIM; 610987; gene. DR OpenTargets; ENSG00000204147; -. DR VEuPathDB; HostDB:ENSG00000204147; -. DR eggNOG; KOG2232; Eukaryota. DR GeneTree; ENSGT00390000015792; -. DR HOGENOM; CLU_086144_1_0_1; -. DR InParanoid; P0C7U1; -. DR OMA; GCQTHIL; -. DR OrthoDB; 191371at2759; -. DR PAN-GO; P0C7U1; 5 GO annotations based on evolutionary models. DR PhylomeDB; P0C7U1; -. DR PathwayCommons; P0C7U1; -. DR Agora; ENSG00000204147; -. DR BioGRID-ORCS; 653308; 12 hits in 1057 CRISPR screens. DR ChiTaRS; ASAH2B; human. DR GeneWiki; ASAH2B; -. DR GenomeRNAi; 653308; -. DR Pharos; P0C7U1; Tdark. DR PRO; PR:P0C7U1; -. DR Proteomes; UP000005640; Chromosome 10. DR RNAct; P0C7U1; protein. DR Bgee; ENSG00000204147; Expressed in duodenum and 107 other cell types or tissues. DR ExpressionAtlas; P0C7U1; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-ARBA. DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-ARBA. DR GO; GO:0017040; F:N-acylsphingosine amidohydrolase activity; IEA:InterPro. DR GO; GO:0046513; P:ceramide biosynthetic process; IEA:UniProtKB-ARBA. DR GO; GO:0046514; P:ceramide catabolic process; IEA:InterPro. DR GO; GO:0046512; P:sphingosine biosynthetic process; IEA:UniProtKB-ARBA. DR FunFam; 2.60.40.2300:FF:000001; N-acylsphingosine amidohydrolase 2; 1. DR Gene3D; 2.60.40.2300; Neutral/alkaline non-lysosomal ceramidase, C-terminal domain; 1. DR InterPro; IPR006823; Ceramidase_alk. DR InterPro; IPR038445; NCDase_C_sf. DR InterPro; IPR031331; NEUT/ALK_ceramidase_C. DR PANTHER; PTHR12670; CERAMIDASE; 1. DR PANTHER; PTHR12670:SF1; NEUTRAL CERAMIDASE; 1. DR Pfam; PF17048; Ceramidse_alk_C; 1. PE 2: Evidence at transcript level; KW Alternative splicing; Reference proteome. FT CHAIN 1..165 FT /note="Putative inactive neutral ceramidase B" FT /id="PRO_0000343741" FT VAR_SEQ 1..29 FT /note="MRQHRQFMDRTHYLLTFSSSETLLRLLLR -> MVANLSRGPEPPFFKQLIV FT PLIPS (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_056938" SQ SEQUENCE 165 AA; 19025 MW; AB59B4F728F82D66 CRC64; MRQHRQFMDR THYLLTFSSS ETLLRLLLRI VDRAPKGRTF GDVLQPAKPE YRVGEVAEVI FVGANPKNSV QNQTHQTFLT VEKYEATSTS WQIVCNDASW ETRFYWHKGL LGLSNATVEW HIPDTAQPGI YRIRYFGHNR KQDILKPAVI LSFEGTSPAF EVVTI // ID PSN1_HUMAN Reviewed; 467 AA. AC P49768; B2R6D3; O95465; Q14762; Q15719; Q15720; Q96P33; Q9UIF0; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1996, sequence version 1. DT 28-JAN-2026, entry version 263. DE RecName: Full=Presenilin-1 {ECO:0000303|PubMed:9144240}; DE Short=PS-1 {ECO:0000303|PubMed:9298817}; DE EC=3.4.23.- {ECO:0000269|PubMed:10206644, ECO:0000269|PubMed:10811883, ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:12679784, ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:26280335}; DE AltName: Full=Protein S182 {ECO:0000303|PubMed:7550356}; DE Contains: DE RecName: Full=Presenilin-1 NTF subunit {ECO:0000305|PubMed:9173929}; DE Contains: DE RecName: Full=Presenilin-1 CTF subunit {ECO:0000305|PubMed:9173929}; DE Contains: DE RecName: Full=Presenilin-1 CTF12 {ECO:0000305|PubMed:9485372}; DE Short=PS1-CTF12; GN Name=PSEN1 {ECO:0000312|HGNC:HGNC:9508}; Synonyms=AD3, PS1, PSNL1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2), VARIANTS AD3 RP LEU-146; ARG-163; GLU-246 AND VAL-286, AND TISSUE SPECIFICITY. RC TISSUE=Brain; RX PubMed=7596406; DOI=10.1038/375754a0; RA Sherrington R., Rogaev E.I., Liang Y., Rogaeva E.A., Levesque G., Ikeda M., RA Chi H., Lin C., Li G., Holman K., Tsuda T., Mar L., Foncin J.-F., RA Bruni A.C., Montesi M.P., Sorbi S., Rainero I., Pinessi L., Nee L., RA Chumakov I., Pollen D., Brookes A., Sanseau P., Polinsky R.J., Wasco W., RA da Silva H.A.R., Haines J.L., Pericak-Vance M.A., Tanzi R.E., Roses A.D., RA Fraser P.E., Rommens J.M., St George-Hyslop P.H.; RT "Cloning of a gene bearing missense mutations in early-onset familial RT Alzheimer's disease."; RL Nature 375:754-760(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), AND TISSUE SPECIFICITY. RC TISSUE=Blood, and Brain; RX PubMed=8641442; DOI=10.1016/0014-5793(96)00054-3; RA Sahara N., Yahagi Y., Takagi H., Kondo T., Okochi M., Usami M., RA Shirasawa T., Mori H.; RT "Identification and characterization of presenilin I-467, I-463 and I- RT 374."; RL FEBS Lett. 381:7-11(1996). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4). RA Powell C.S., Gegg M.E., Palmer M.S.; RT "Human presenilin 1 gene encodes an alternative protein-minilin."; RL Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Rowen L., Madan A., Qin S., Abbasi N., Dors M., Ratcliffe A., Madan A., RA Dickhoff R., Shaffer T., James R., Lasky S., Hood L.; RT "Complete sequence of the gene for presenilin 1."; RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5). RA Kang L., Zhang B., Zhou Y., Peng X., Yuan J., Qiang B.; RL Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Tongue; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12508121; DOI=10.1038/nature01348; RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., RA Waterston R., Hood L., Weissenbach J.; RT "The DNA sequence and analysis of human chromosome 14."; RL Nature 421:601-607(2003). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-113. RX PubMed=9070286; DOI=10.1006/bbrc.1996.6043; RA Tsujimura A., Yasojima K., Hashimoto-Gotoh T.; RT "Cloning of Xenopus presenilin-alpha and -beta cDNAs and their differential RT expression in oogenesis and embryogenesis."; RL Biochem. Biophys. Res. Commun. 231:392-396(1997). RN [11] RP NUCLEOTIDE SEQUENCE [MRNA] OF 24-32, AND ALTERNATIVE SPLICING (ISOFORMS 6 RP AND 7). RC TISSUE=Megakaryocyte, and Platelet; RX PubMed=8804415; DOI=10.1016/0014-5793(96)00845-9; RA Vidal R., Ghiso J., Wisniewski T., Frangione B.; RT "Alzheimer's presenilin 1 gene expression in platelets and megakaryocytes. RT Identification of a novel splice variant."; RL FEBS Lett. 393:19-23(1996). RN [12] RP PROTEIN SEQUENCE OF 36-42; 61-76; 109-129; 217-239; 270-278; 315-320; RP 345-352 AND 381-395 (ISOFORM 1), IDENTIFICATION BY MASS SPECTROMETRY, RP IDENTIFICATION IN GAMMA-SECRETASE COMPLEX, FUNCTION, CATALYTIC ACTIVITY, RP AND SUBCELLULAR LOCATION. RX PubMed=15274632; DOI=10.1021/bi0494976; RA Fraering P.C., Ye W., Strub J.-M., Dolios G., LaVoie M.J., RA Ostaszewski B.L., van Dorsselaer A., Wang R., Selkoe D.J., Wolfe M.S.; RT "Purification and characterization of the human gamma-secretase complex."; RL Biochemistry 43:9774-9789(2004). RN [13] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=8574969; DOI=10.1038/nm0296-224; RA Kovacs D.M., Fausett H.J., Page K.J., Kim T.-W., Moir R.D., Merriam D.E., RA Hollister R.D., Hallmark O.G., Mancini R., Felsenstein K.M., Hyman B.T., RA Tanzi R.E., Wasco W.; RT "Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and RT localization to intracellular membranes in mammalian cells."; RL Nat. Med. 2:224-229(1996). RN [14] RP PROTEOLYTIC PROCESSING. RX PubMed=9173929; DOI=10.1006/nbdi.1997.0129; RA Podlisny M.B., Citron M., Amarante P., Sherrington R., Xia W., Zhang J., RA Diehl T., Levesque G., Fraser P., Haass C., Koo E.H., Seubert P., RA St George-Hyslop P.H., Teplow D.B., Selkoe D.J.; RT "Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 RT and Ala299 and occur as stable N- and C-terminal fragments in normal and RT Alzheimer brain tissue."; RL Neurobiol. Dis. 3:325-337(1997). RN [15] RP PHOSPHORYLATION. RX PubMed=9144240; DOI=10.1073/pnas.94.10.5349; RA Walter J., Gruenberg J., Capell A., Pesold B., Schindzielorz A., Citron M., RA Mendla K., St George-Hyslop P.H., Multhaup G., Selkoe D.J., Haass C.; RT "Proteolytic processing of the Alzheimer disease-associated presenilin-1 RT generates an in vivo substrate for protein kinase C."; RL Proc. Natl. Acad. Sci. U.S.A. 94:5349-5354(1997). RN [16] RP CASPASE CLEAVAGE SITE, AND MUTAGENESIS OF ASP-345; ASP-373 AND ASP-385. RX PubMed=9485372; DOI=10.1021/bi972106l; RA Gruenberg J., Walter J., Loetscher H., Deuschle U., Jacobsen H., Haass C.; RT "Alzheimer's disease associated presenilin-1 holoprotein and its 18-20 kDa RT C-terminal fragment are death substrates for proteases of the caspase RT family."; RL Biochemistry 37:2263-2270(1998). RN [17] RP FUNCTION, INTERACTION WITH CTNNB1, AND SUBCELLULAR LOCATION. RX PubMed=9738936; DOI=10.1016/s0014-5793(98)00886-2; RA Murayama M., Tanaka S., Palacino J., Murayama O., Honda T., Sun X., RA Yasutake K., Nihonmatsu N., Wolozin B., Takashima A.; RT "Direct association of presenilin-1 with beta-catenin."; RL FEBS Lett. 433:73-77(1998). RN [18] RP INTERACTION WITH FLNA AND FLNB. RX PubMed=9437013; DOI=10.1523/jneurosci.18-03-00914.1998; RA Zhang W., Han S.W., McKeel D.W., Goate A., Wu J.Y.; RT "Interaction of presenilins with the filamin family of actin-binding RT proteins."; RL J. Neurosci. 18:914-922(1998). RN [19] RP FUNCTION, MUTAGENESIS OF MET-292, AND PROTEOLYTIC PROCESSING. RX PubMed=10545183; DOI=10.1021/bi9914210; RA Steiner H., Romig H., Pesold B., Philipp U., Baader M., Citron M., RA Loetscher H., Jacobsen H., Haass C.; RT "Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 RT in the absence of endoproteolysis."; RL Biochemistry 38:14600-14605(1999). RN [20] RP INTERACTION WITH MTCH1. RX PubMed=10551805; DOI=10.1074/jbc.274.46.32543; RA Xu X., Shi Y.-C., Wu X., Gambetti P., Sui D., Cui M.-Z.; RT "Identification of a novel PSD-95/Dlg/ZO-1 (PDZ)-like protein interacting RT with the C terminus of presenilin-1."; RL J. Biol. Chem. 274:32543-32546(1999). RN [21] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH NOTCH. RX PubMed=10593990; DOI=10.1074/jbc.274.51.36801; RA Ray W.J., Yao M., Mumm J., Schroeter E.H., Saftig P., Wolfe M., RA Selkoe D.J., Kopan R., Goate A.M.; RT "Cell surface presenilin-1 participates in the gamma-secretase-like RT proteolysis of Notch."; RL J. Biol. Chem. 274:36801-36807(1999). RN [22] RP INTERACTION WITH CTNND2 AND CTNNB1, AND SUBCELLULAR LOCATION. RX PubMed=10037471; DOI=10.1046/j.1471-4159.1999.0720999.x; RA Levesque G., Yu G., Nishimura M., Zhang D.M., Levesque L., Yu H., Xu D., RA Liang Y., Rogaeva E.A., Ikeda M., Duthie M., Murgolo N., Wang L., RA VanderVere P., Bayne M.L., Strader C.D., Rommens J.M., Fraser P.E., RA St George-Hyslop P.H.; RT "Presenilins interact with armadillo proteins including neural-specific RT plakophilin-related protein and beta-catenin."; RL J. Neurochem. 72:999-1008(1999). RN [23] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF ASP-257 AND RP ASP-385. RX PubMed=10206644; DOI=10.1038/19077; RA Wolfe M.S., Xia W., Ostaszewski B.L., Diehl T.S., Kimberly W.T., RA Selkoe D.J.; RT "Two transmembrane aspartates in presenilin-1 required for presenilin RT endoproteolysis and gamma-secretase activity."; RL Nature 398:513-517(1999). RN [24] RP INTERACTION WITH DOCK3. RX PubMed=10854253; DOI=10.1046/j.1471-4159.2000.0750109.x; RA Kashiwa A., Yoshida H., Lee S., Paladino T., Liu Y., Chen Q., Dargusch R., RA Schubert D., Kimura H.; RT "Isolation and characterization of novel presenilin binding protein."; RL J. Neurochem. 75:109-116(2000). RN [25] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF ASP-257 AND RP ASP-385. RX PubMed=10899933; DOI=10.1046/j.1471-4159.2000.0750583.x; RA Berezovska O., Jack C., McLean P., Aster J.C., Hicks C., Xia W., RA Wolfe M.S., Kimberly W.T., Weinmaster G., Selkoe D.J., Hyman B.T.; RT "Aspartate mutations in presenilin and gamma-secretase inhibitors both RT impair notch1 proteolysis and nuclear translocation with relative RT preservation of notch1 signaling."; RL J. Neurochem. 75:583-593(2000). RN [26] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF LEU-286. RX PubMed=10811883; DOI=10.1073/pnas.100049897; RA Kulic L., Walter J., Multhaup G., Teplow D.B., Baumeister R., Romig H., RA Capell A., Steiner H., Haass C.; RT "Separation of presenilin function in amyloid beta-peptide generation and RT endoproteolysis of Notch."; RL Proc. Natl. Acad. Sci. U.S.A. 97:5913-5918(2000). RN [27] RP INTERACTION WITH PARL. RX PubMed=12214059; DOI=10.3233/jad-2001-3203; RA Pellegrini L., Passer B.J., Canelles M., Lefterov I., Ganjei J.K., RA Fowlkes B.J., Koonin E.V., D'Adamio L.; RT "PAMP and PARL, two novel putative metalloproteases interacting with the RT COOH-terminus of presenilin-1 and -2."; RL J. Alzheimers Dis. 3:181-190(2001). RN [28] RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=11987239; DOI=10.1006/bcmd.2002.0486; RA Mirinics Z.K., Calafat J., Udby L., Lovelock J., Kjeldsen L., RA Rothermund K., Sisodia S.S., Borregaard N., Corey S.J.; RT "Identification of the presenilins in hematopoietic cells with localization RT of presenilin 1 to neutrophil and platelet granules."; RL Blood Cells Mol. Dis. 28:28-38(2002). RN [29] RP FUNCTION, SUBCELLULAR LOCATION, AND IDENTIFICATION IN A COMPLEX WITH CDH1 RP AND CTNNB1. RX PubMed=11953314; DOI=10.1093/emboj/21.8.1948; RA Marambaud P., Shioi J., Serban G., Georgakopoulos A., Sarner S., Nagy V., RA Baki L., Wen P., Efthimiopoulos S., Shao Z., Wisniewski T., Robakis N.K.; RT "A presenilin-1/gamma-secretase cleavage releases the E-cadherin RT intracellular domain and regulates disassembly of adherens junctions."; RL EMBO J. 21:1948-1956(2002). RN [30] RP INTERACTION WITH HERPUD1. RX PubMed=11799129; DOI=10.1074/jbc.m112372200; RA Sai X., Kawamura Y., Kokame K., Yamaguchi H., Shiraishi H., Suzuki R., RA Suzuki T., Kawaichi M., Miyata T., Kitamura T., De Strooper B., RA Yanagisawa K., Komano H.; RT "Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin- RT mediated generation of amyloid beta-protein."; RL J. Biol. Chem. 277:12915-12920(2002). RN [31] RP INTERACTION WITH GFAP, MUTAGENESIS OF 66-ASP--ASP-72; 76-LYS-TYR-77; RP 82-VAL-ILE-83; VAL-82 AND 84-MET-LEU-85, AND CHARACTERIZATION OF VARIANTS RP AD3 VAL-79 AND LEU-82. RX PubMed=12058025; DOI=10.1074/jbc.m112121200; RA Nielsen A.L., Holm I.E., Johansen M., Bonven B., Jorgensen P., RA Jorgensen A.L.; RT "A new splice variant of glial fibrillary acidic protein GFAPepsilon, RT interacts with the presenilin proteins."; RL J. Biol. Chem. 277:29983-29991(2002). RN [32] RP INTERACTION WITH CDH2, SUBCELLULAR LOCATION, AND MUTAGENESIS OF ASP-385. RX PubMed=14515347; DOI=10.1002/jnr.10753; RA Uemura K., Kitagawa N., Kohno R., Kuzuya A., Kageyama T., Chonabayashi K., RA Shibasaki H., Shimohama S.; RT "Presenilin 1 is involved in maturation and trafficking of N-cadherin to RT the plasma membrane."; RL J. Neurosci. Res. 74:184-191(2003). RN [33] RP ENZYME ACTIVITY OF A GAMMA-SECRETASE COMPLEX, CATALYTIC ACTIVITY, FUNCTION, RP AND SUBUNIT. RX PubMed=12679784; DOI=10.1038/ncb960; RA Edbauer D., Winkler E., Regula J.T., Pesold B., Steiner H., Haass C.; RT "Reconstitution of gamma-secretase activity."; RL Nat. Cell Biol. 5:486-488(2003). RN [34] RP COMPONENT OF A GAMMA-SECRETASE COMPLEX WITH PEN2; PSEN1/PSEN2 AND NCSTN. RX PubMed=12740439; DOI=10.1073/pnas.1037392100; RA Kimberly W.T., LaVoie M.J., Ostaszewski B.L., Ye W., Wolfe M.S., RA Selkoe D.J.; RT "Gamma-secretase is a membrane protein complex comprised of presenilin, RT nicastrin, Aph-1, and Pen-2."; RL Proc. Natl. Acad. Sci. U.S.A. 100:6382-6387(2003). RN [35] RP SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S). RX PubMed=14759258; DOI=10.1186/gb-2004-5-2-r8; RA Hillman R.T., Green R.E., Brenner S.E.; RT "An unappreciated role for RNA surveillance."; RL Genome Biol. 5:R8.1-R8.16(2004). RN [36] RP FUNCTION, SUBCELLULAR LOCATION, VARIANT AD3 SER-117, AND CHARACTERIZATION RP OF VARIANTS AD3 LEU-117 AND SER-117. RX PubMed=15004326; DOI=10.3233/jad-2004-6105; RA Dowjat W.K., Kuchna I., Wisniewski T., Wegiel J.; RT "A novel highly pathogenic Alzheimer presenilin-1 mutation in codon 117 RT (Pro117Ser): Comparison of clinical, neuropathological and cell culture RT phenotypes of Pro117Leu and Pro117Ser mutations."; RL J. Alzheimers Dis. 6:31-43(2004). RN [37] RP PHOSPHORYLATION AT SER-310 AND SER-346, AND MUTAGENESIS OF SER-310 AND RP SER-346. RX PubMed=14576165; DOI=10.1074/jbc.m306653200; RA Fluhrer R., Friedlein A., Haass C., Walter J.; RT "Phosphorylation of presenilin 1 at the caspase recognition site regulates RT its proteolytic processing and the progression of apoptosis."; RL J. Biol. Chem. 279:1585-1593(2004). RN [38] RP TOPOLOGY. RX PubMed=15385547; DOI=10.1074/jbc.m407898200; RA Friedmann E., Lemberg M.K., Weihofen A., Dev K.K., Dengler U., Rovelli G., RA Martoglio B.; RT "Consensus analysis of signal peptide peptidase and homologous human RT aspartic proteases reveals opposite topology of catalytic domains compared RT with presenilins."; RL J. Biol. Chem. 279:50790-50798(2004). RN [39] RP FUNCTION, ACTIVE SITES ASP-257 AND ASP-385, AND MUTAGENESIS OF TYR-256; RP ASP-257; ASP-385 AND TYR-389. RX PubMed=15341515; DOI=10.1111/j.1471-4159.2004.02596.x; RA Wrigley J.D., Nunn E.J., Nyabi O., Clarke E.E., Hunt P., Nadin A., RA De Strooper B., Shearman M.S., Beher D.; RT "Conserved residues within the putative active site of gamma-secretase RT differentially influence enzyme activity and inhibitor binding."; RL J. Neurochem. 90:1312-1320(2004). RN [40] RP INTERACTION WITH CDH1 AND CTNNB1. RX PubMed=16126725; DOI=10.1074/jbc.m507503200; RA Serban G., Kouchi Z., Baki L., Georgakopoulos A., Litterst C.M., Shioi J., RA Robakis N.K.; RT "Cadherins mediate both the association between PS1 and beta-catenin and RT the effects of PS1 on beta-catenin stability."; RL J. Biol. Chem. 280:36007-36012(2005). RN [41] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [42] RP FUNCTION, AND CHARACTERIZATION OF VARIANT AD3 VAL-146. RX PubMed=16959576; DOI=10.1016/j.cell.2006.06.059; RA Tu H., Nelson O., Bezprozvanny A., Wang Z., Lee S.F., Hao Y.H., RA Serneels L., De Strooper B., Yu G., Bezprozvanny I.; RT "Presenilins form ER Ca2+ leak channels, a function disrupted by familial RT Alzheimer's disease-linked mutations."; RL Cell 126:981-993(2006). RN [43] RP FUNCTION OF PAL MOTIF, MUTAGENESIS OF PRO-433; ALA-434 AND LEU-435, AND RP CHARACTERIZATION OF VARIANT AD3 PHE-435. RX PubMed=16305624; DOI=10.1111/j.1471-4159.2005.03548.x; RA Wang J., Beher D., Nyborg A.C., Shearman M.S., Golde T.E., Goate A.; RT "C-terminal PAL motif of presenilin and presenilin homologues required for RT normal active site conformation."; RL J. Neurochem. 96:218-227(2006). RN [44] RP VARIANTS AD3 ILE-139 AND CYS-289. RX PubMed=8875251; DOI=10.1093/hmg/5.supplement_1.1449; RA Cruts M., Hendriks L., Van Broeckhoven C.; RT "The presenilin genes: a new gene family involved in Alzheimer disease RT pathology."; RL Hum. Mol. Genet. 5:1449-1455(1996). RN [45] RP REVIEW ON VARIANTS. RX PubMed=9521418; RX DOI=10.1002/(sici)1098-1004(1998)11:3<183::aid-humu1>3.0.co;2-j; RA Cruts M., van Broeckhoven C.; RT "Presenilin mutations in Alzheimer's disease."; RL Hum. Mutat. 11:183-190(1998). RN [46] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [47] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [48] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [49] RP IDENTIFICATION IN THE GAMMA-SECRETASE COMPLEX, AND INTERACTION WITH CRB2. RX PubMed=20299451; DOI=10.1074/jbc.m109.038760; RA Mitsuishi Y., Hasegawa H., Matsuo A., Araki W., Suzuki T., Tagami S., RA Okochi M., Takeda M., Roepman R., Nishimura M.; RT "Human CRB2 inhibits gamma-secretase cleavage of amyloid precursor protein RT by binding to the presenilin complex."; RL J. Biol. Chem. 285:14920-14931(2010). RN [50] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [51] RP INVOLVEMENT IN ACNINV3. RX PubMed=20929727; DOI=10.1126/science.1196284; RA Wang B., Yang W., Wen W., Sun J., Su B., Liu B., Ma D., Lv D., Wen Y., RA Qu T., Chen M., Sun M., Shen Y., Zhang X.; RT "Gamma-secretase gene mutations in familial acne inversa."; RL Science 330:1065-1065(2010). RN [52] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43 AND SER-367, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [53] RP SUBCELLULAR LOCATION, AND INTERACTION WITH UBQLN1. RX PubMed=21143716; DOI=10.1111/j.1600-0854.2010.01149.x; RA Viswanathan J., Haapasalo A., Bottcher C., Miettinen R., Kurkinen K.M., RA Lu A., Thomas A., Maynard C.J., Romano D., Hyman B.T., Berezovska O., RA Bertram L., Soininen H., Dantuma N.P., Tanzi R.E., Hiltunen M.; RT "Alzheimer's disease-associated ubiquilin-1 regulates presenilin-1 RT accumulation and aggresome formation."; RL Traffic 12:330-348(2011). RN [54] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43 AND SER-367, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [55] RP FUNCTION, INTERACTION WITH APH1A/APH1B AND PEN2, SUBCELLULAR LOCATION, AND RP CHARACTERIZATION OF VARIANT AD3 ASP-206. RX PubMed=25394380; DOI=10.1007/s12035-014-8969-1; RA Chen W.T., Hsieh Y.F., Huang Y.J., Lin C.C., Lin Y.T., Liu Y.C., Lien C.C., RA Cheng I.H.; RT "G206D mutation of presenilin-1 reduces Pen2 interaction, increases RT Abeta42/Abeta40 ratio and elevates ER Ca(2+) accumulation."; RL Mol. Neurobiol. 52:1835-1849(2015). RN [56] {ECO:0007744|PDB:2KR6} RP STRUCTURE BY NMR OF 292-467. RA Doetsch V.; RT "Solution structure of presenilin-1 CTF subunit."; RL Submitted (DEC-2009) to the PDB data bank. RN [57] RP STRUCTURE BY ELECTRON MICROSCOPY (4.5 ANGSTROMS), FUNCTION, SUBCELLULAR RP LOCATION, SUBUNIT, AND TOPOLOGY. RX PubMed=25043039; DOI=10.1038/nature13567; RA Lu P., Bai X.C., Ma D., Xie T., Yan C., Sun L., Yang G., Zhao Y., Zhou R., RA Scheres S.H., Shi Y.; RT "Three-dimensional structure of human gamma-secretase."; RL Nature 512:166-170(2014). RN [58] {ECO:0007744|PDB:5FN2, ECO:0007744|PDB:5FN3, ECO:0007744|PDB:5FN4, ECO:0007744|PDB:5FN5} RP STRUCTURE BY ELECTRON MICROSCOPY (4.00 ANGSTROMS), SUBUNIT, AND TOPOLOGY. RX PubMed=26623517; DOI=10.7554/elife.11182; RA Bai X.C., Rajendra E., Yang G., Shi Y., Scheres S.H.; RT "Sampling the conformational space of the catalytic subunit of human gamma- RT secretase."; RL Elife 4:0-0(2015). RN [59] {ECO:0007744|PDB:5A63} RP STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, RP TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF RP VARIANTS AD3 LEU-213; ILE-237 AND PHE-261, AND MUTAGENESIS OF ILE-202; RP LEU-226; LEU-248 AND LEU-424. RX PubMed=26280335; DOI=10.1038/nature14892; RA Bai X.C., Yan C., Yang G., Lu P., Ma D., Sun L., Zhou R., Scheres S.H., RA Shi Y.; RT "An atomic structure of human gamma-secretase."; RL Nature 525:212-217(2015). RN [60] {ECO:0007744|PDB:4UIS} RP STRUCTURE BY ELECTRON MICROSCOPY (4.40 ANGSTROMS) OF 81-463, SUBUNIT, AND RP TOPOLOGY. RX PubMed=25918421; DOI=10.1073/pnas.1506242112; RA Sun L., Zhao L., Yang G., Yan C., Zhou R., Zhou X., Xie T., Zhao Y., Wu S., RA Li X., Shi Y.; RT "Structural basis of human gamma-secretase assembly."; RL Proc. Natl. Acad. Sci. U.S.A. 112:6003-6008(2015). RN [61] RP STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS) OF MUTANT ALA-385 IN RP COMPLEX WITH NOTCH1; PSENEN; APH1A AND NCSTN, SUBUNIT, TOPOLOGY, CATALYTIC RP ACTIVITY, FUNCTION, ACTIVE SITE, MUTAGENESIS OF GLN-112; 288-TYR--SER-290; RP 377-ARG--LEU-381; ASP-385; LEU-432 AND 432-LEU--ALA-434, AND DOMAIN. RX PubMed=30598546; DOI=10.1038/s41586-018-0813-8; RA Yang G., Zhou R., Zhou Q., Guo X., Yan C., Ke M., Lei J., Shi Y.; RT "Structural basis of Notch recognition by human gamma-secretase."; RL Nature 565:192-197(2019). RN [62] RP STRUCTURE BY ELECTRON MICROSCOPY (2.60 ANGSTROMS) OF MUTANT ALA-385 IN RP COMPLEX WITH APP CHAIN C83; PSENEN; APH1A AND NCSTN, SUBUNIT, TOPOLOGY, RP CATALYTIC ACTIVITY, FUNCTION, ACTIVE SITE, DOMAIN, AND MUTAGENESIS OF RP GLN-112; 288-TYR--SER-290; 377-ARG--LEU-381; ASP-385; LEU-432 AND RP 432-LEU--ALA-434. RX PubMed=30630874; DOI=10.1126/science.aaw0930; RA Zhou R., Yang G., Guo X., Zhou Q., Lei J., Shi Y.; RT "Recognition of the amyloid precursor protein by human gamma-secretase."; RL Science 0:0-0(2019). RN [63] RP VARIANTS AD3 THR-143 AND ALA-384. RX PubMed=8634711; DOI=10.1093/hmg/4.12.2363; RA Cruts M., Backhovens H., Wang S.-Y., van Gassen G., Theuns J., RA de Jonghe C., Wehnert A., de Voecht J., de Winter G., Cras P., Bruyland M., RA Datson N., Weissenbach J., den Dunnen J.T., Martin J.-J., Hendriks L., RA Van Broeckhoven C.; RT "Molecular genetic analysis of familial early-onset Alzheimer's disease RT linked to chromosome 14q24.3."; RL Hum. Mol. Genet. 4:2363-2372(1995). RN [64] RP VARIANTS AD3 LEU-82; HIS-115; THR-139; ARG-163; THR-231; LEU-264; VAL-392 RP AND TYR-410. RX PubMed=8634712; DOI=10.1093/hmg/4.12.2373; RA Campion D., Flaman J.-M., Brice A., Hannequin D., Dubois B., Martin C., RA Moreau V., Charbonnier F., Didierjean O., Tardieu S., Penet C., Puel M., RA Pasquier F., le Doze F., Bellis G., Calenda A., Heilig R., Martinez M., RA Mallet J., Bellis M., Clerget-Darpoux F., Agid Y., Frebourg T.; RT "Mutations of the presenilin I gene in families with early-onset RT Alzheimer's disease."; RL Hum. Mol. Genet. 4:2373-2377(1995). RN [65] RP VARIANTS AD3 VAL-260; VAL-285 AND VAL-392. RX PubMed=7651536; DOI=10.1038/376775a0; RA Rogaev E.I., Sherrington R., Rogaeva E.A., Levesque G., Ikeda M., Liang Y., RA Chi H., Lin C., Holman K., Tsuda T., Mar L., Sorbi S., Nacmias B., RA Piacentini S., Amaducci L., Chumakov I., Cohen D., Lannfelt L., RA Fraser P.E., Rommens J.M., St George-Hyslop P.H.; RT "Familial Alzheimer's disease in kindreds with missense mutations in a gene RT on chromosome 1 related to the Alzheimer's disease type 3 gene."; RL Nature 376:775-778(1995). RN [66] RP VARIANTS AD3 VAL-139; VAL-146; TYR-163; SER-267; ALA-280 AND GLY-280. RX PubMed=7550356; DOI=10.1038/ng1095-219; RA Clark R.F., Hutton M., Fuldner R.A., Froelich S., Karran E., Talbot C., RA Crook R., Lendon C.L., Prihar G., He C., Korenblat K., Martinez A., RA Wragg M., Busfield F., Behrens M.I., Myers A., Norton J., Morris J., RA Mehta N., Pearson C., Lincoln S., Baker M., Duff K., Zehr C., Perez-Tur J., RA Houlden H., Ruiz A., Ossa J., Lopera F., Arcos M., Madrigal L., RA Collinge J., Humphreys C., Asworth T., Sarner S., Fox N.C., Harvey R., RA Kennedy A., Roques P.K., Cline R.T., Phillips C.A., Venter J.C., Forsel L., RA Axelman K., Lilius L., Johnston J., Cowburn R., Viitanen M., Winblad B., RA Kosik K.S., Haltia M., Poyhonen M., Dickson D., Mann D., Neary D., RA Snowden J., Lantos P., Lannfelt L., Rossor M.N., Roberts G.W., Adams M.D., RA Hardy J., Goate A.M.; RT "The structure of the presenilin 1 (S182) gene and identification of six RT novel mutations in early onset AD families."; RL Nat. Genet. 11:219-222(1995). RN [67] RP VARIANT AD3 ALA-280, AND INVOLVEMENT IN AD3. RX PubMed=8837617; DOI=10.1038/nm1096-1146; RA Lemere C.A., Lopera F., Kosik K.S., Lendon C.L., Ossa J., Saido T.C., RA Yamaguchi H., Ruiz A., Martinez A., Madrigal L., Hincapie L., Arango J.C., RA Anthony D.C., Koo E.H., Goate A.M., Selkoe D.J., Arango J.C.; RT "The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 RT deposition and severe cerebellar pathology."; RL Nat. Med. 2:1146-1150(1996). RN [68] RP VARIANTS AD3 PHE-96; ARG-163 AND THR-213. RX PubMed=8733303; DOI=10.1016/0304-3940(96)12587-8; RA Kamino K., Sato S., Sakaki Y., Yoshiiwa A., Nishiwaki Y., Takeda H., RA Tanabe H., Nishimura T., Li K., St George-Hyslop P.H., Miki T., Ogihara T.; RT "Three different mutations of presenilin 1 gene in early-onset Alzheimer's RT disease families."; RL Neurosci. Lett. 208:195-198(1996). RN [69] RP VARIANT AD3 ASP-135. RX PubMed=9225696; DOI=10.1002/ana.410420121; RA Crook R., Ellis R., Shanks M., Thal L.J., Perez-Tur J., Baker M., RA Hutton M., Haltia T., Hardy J., Galasko D.; RT "Early-onset Alzheimer's disease with a presenilin-1 mutation at the site RT corresponding to the Volga German presenilin-2 mutation."; RL Ann. Neurol. 42:124-128(1997). RN [70] RP VARIANT AD3 ALA-280. RX PubMed=9298817; RX DOI=10.1002/(sici)1098-1004(1997)10:3<186::aid-humu2>3.0.co;2-h; RA Lendon C.L., Martinez A., Behrens I.M., Kosik K.S., Madrigal L., Norton J., RA Neuman R., Myers A., Busfield F., Wragg M., Arcos M., Arango-Viana J.C., RA Ossa J., Ruiz A., Goate A.M., Lopera F.; RT "E280A PS-1 mutation causes Alzheimer's disease but age of onset is not RT modified by ApoE alleles."; RL Hum. Mutat. 10:186-195(1997). RN [71] RP VARIANTS AD3 THR-233 AND THR-278. RX PubMed=9172170; DOI=10.1097/00001756-199704140-00043; RA Kwok J.B.J., Taddei K., Hallupp M., Fisher C., Brooks W.S., Broe G.A., RA Hardy J., Fulham M.J., Nicholson G.A., Stell R., St George-Hyslop P.H., RA Fraser P.E., Kakulas B., Clarnette R., Relkin N., Gandy S.E., RA Schofield P.R., Martins R.N.; RT "Two novel (M233T and R278T) presenilin-1 mutations in early-onset RT Alzheimer's disease pedigrees and preliminary evidence for association of RT presenilin-1 mutations with a novel phenotype."; RL NeuroReport 8:1537-1542(1997). RN [72] RP VARIANT AD3 PRO-171. RX PubMed=9833068; RA Ramirez-Duenas M.G., Rogaeva E.A., Leal C.A., Lin C., RA Ramirez-Casillas G.A., Hernandez-Romo J.A., St George-Hyslop P.H., RA Cantu J.M.; RT "A novel Leu171Pro mutation in presenilin-1 gene in a Mexican family with RT early onset Alzheimer disease."; RL Ann. Genet. 41:149-153(1998). RN [73] RP VARIANT GLY-318. RX PubMed=9851443; DOI=10.1002/ana.410440617; RA Mattila K.M., Forsell C., Pirttila T., Rinne J.O., Lehtimaki T., Roytta M., RA Lilius L., Eerola A., St George-Hyslop P.H., Frey H., Lannfelt L.; RT "The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause RT Alzheimer's disease."; RL Ann. Neurol. 44:965-967(1998). RN [74] RP VARIANT GLY-318. RX PubMed=9851450; DOI=10.1002/ana.410440624; RA Aldudo J., Bullido M.J., Frank A., Valdivieso F.; RT "Missense mutation E318G of the presenilin-1 gene appears to be a RT nonpathogenic polymorphism."; RL Ann. Neurol. 44:985-986(1998). RN [75] RP VARIANTS AD3 VAL-79; CYS-115 AND VAL-231, AND VARIANT GLY-318. RX PubMed=9384602; DOI=10.1093/hmg/7.1.43; RA Cruts M., van Duijn C.M., Backhovens H., van den Broeck M., Wehnert A., RA Serneels S., Sherrington R., Hutton M., Hardy J., St George-Hyslop P.H., RA Hofman A., van Broeckhoven C.; RT "Estimation of the genetic contribution of presenilin-1 and -2 mutations in RT a population-based study of presenile Alzheimer disease."; RL Hum. Mol. Genet. 7:43-51(1998). RN [76] RP VARIANTS AD3 ASP-120; ARG-163; VAL-209; VAL-260; LEU-264; TYR-410 AND RP PRO-426. RX PubMed=9521423; RX DOI=10.1002/(sici)1098-1004(1998)11:3<216::aid-humu6>3.0.co;2-f; RA Poorkaj P., Sharma V., Anderson L., Nemens E., Alonso M.E., Orr H., RA White J., Heston L., Bird T.D., Schellenberg G.D.; RT "Missense mutations in the chromosome 14 familial Alzheimer's disease RT presenilin 1 gene."; RL Hum. Mutat. 11:216-221(1998). RN [77] RP VARIANT AD3 GLU-378. RX PubMed=10200054; RX DOI=10.1002/(sici)1098-1004(1998)11:6<481::aid-humu12>3.0.co;2-q; RA Besancon R., Lorenzi A., Cruts M., Radawiec S., Sturtz F., Broussolle E., RA Chazot G., van Broeckhoven C., Chamba G., Vandenberghe A.; RT "Missense mutation in exon 11 (codon 378) of the presenilin-1 gene in a RT French family with early-onset Alzheimer's disease and transmission study RT by mismatch enhanced allele specific amplification."; RL Hum. Mutat. 11:481-481(1998). RN [78] RP VARIANT AD3 LYS-139. RX PubMed=9719376; DOI=10.1136/jmg.35.8.672; RA Dumanchin C., Brice A., Campion D., Hannequin D., Martin C., Moreau V., RA Agid Y., Martinez M., Clerget-Darpoux F., Frebourg T.; RT "De novo presenilin 1 mutations are rare in clinically sporadic, early RT onset Alzheimer's disease cases."; RL J. Med. Genet. 35:672-673(1998). RN [79] RP VARIANT AD3 LEU-117. RX PubMed=9507958; DOI=10.1097/00001756-199801260-00008; RA Wisniewski T., Dowjat W.K., Buxbaum J.D., Khorkova O., Efthimiopoulos S., RA Kulczycki J., Lojkowska W., Wegiel J., Wisniewski H.M., Frangione B.; RT "A novel Polish presenilin-1 mutation (P117L) is associated with familial RT Alzheimer's disease and leads to death as early as the age of 28 years."; RL NeuroReport 9:217-221(1998). RN [80] RP VARIANTS AD3 LEU-169 AND GLN-436. RX PubMed=9831473; DOI=10.1097/00001756-199810050-00034; RA Taddei K., Kwok J.B., Kril J.J., Halliday G.M., Creasey H., Hallupp M., RA Fisher C., Brooks W.S., Chung C., Andrews C., Masters C.L., Schofield P.R., RA Martins R.N.; RT "Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with RT very early onset Alzheimer's disease."; RL NeuroReport 9:3335-3339(1998). RN [81] RP VARIANT GLY-318. RX PubMed=9915968; DOI=10.1086/302200; RA Dermaut B., Cruts M., Slooter A.J.C., van Gestel S., de Jonghe C., RA Vanderstichele H., Vanmechelen E., Breteler M.M., Hofman A., RA van Duijn C.M., van Broeckhoven C.; RT "The Glu318Gly substitution in presenilin 1 is not causally related to RT Alzheimer disease."; RL Am. J. Hum. Genet. 64:290-292(1999). RN [82] RP VARIANTS AD3 LEU-82; HIS-115; ASP-120; THR-139; LEU-146; ILE-147; ARG-163; RP CYS-165; TRP-173; THR-231; THR-233; PRO-235; LEU-264; ILE-390; VAL-392 AND RP TYR-410, AND VARIANT GLY-318. RX PubMed=10441572; DOI=10.1086/302553; RA Campion D., Dumanchin C., Hannequin D., Dubois B., Belliard S., Puel M., RA Thomas-Anterion C., Michon A., Martin C., Charbonnier F., Raux G., RA Camuzat A., Penet C., Mesnage V., Martinez M., Clerget-Darpoux F., RA Brice A., Frebourg T.; RT "Early-onset autosomal dominant Alzheimer disease: prevalence, genetic RT heterogeneity, and mutation spectrum."; RL Am. J. Hum. Genet. 65:664-670(1999). RN [83] RP VARIANTS AD3 PHE-143 AND SER-436. RX PubMed=10090481; RX DOI=10.1002/(sici)1098-1004(1999)13:3<256::aid-humu11>3.0.co;2-p; RA Palmer M.S., Beck J.A., Campbell T.A., Humphries C.B., Roques P.K., RA Fox N.C., Harvey R., Rossor M.N., Collinge J.; RT "Pathogenic presenilin 1 mutations (P436S and I143F) in early-onset RT Alzheimer's disease in the UK."; RL Hum. Mutat. 13:256-256(1999). RN [84] RP VARIANT AD3 ARG-209. RX PubMed=10447269; RX DOI=10.1002/(sici)1098-1004(1999)14:1<90::aid-humu19>3.0.co;2-s; RA Sugiyama N., Suzuki K., Matsumura T., Kawanishi C., Onishi H., Yamada Y., RA Iseki E., Kosaka K.; RT "A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene in a RT Japanese family with presenile familial Alzheimer's disease."; RL Hum. Mutat. 14:90-90(1999). RN [85] RP VARIANTS AD3 LEU-233; ARG-282 AND THR-409, AND VARIANT GLY-318. RX PubMed=10533070; RX DOI=10.1002/(sici)1098-1004(199911)14:5<433::aid-humu10>3.0.co;2-k; RA Aldudo J., Bullido M.J., Valdivieso F.; RT "DGGE method for the mutational analysis of the coding and proximal RT promoter regions of the Alzheimer's disease presenilin-1 gene: two novel RT mutations."; RL Hum. Mutat. 14:433-439(1999). RN [86] RP VARIANT AD3 PRO-169. RX PubMed=10025789; DOI=10.1212/wnl.52.3.566; RA Ezquerra M., Carnero C., Blesa R., Gelpi J.L., Ballesta F., Oliva R.; RT "A presenilin 1 mutation (Ser169Pro) associated with early-onset AD and RT myoclonic seizures."; RL Neurology 52:566-570(1999). RN [87] RP VARIANT AD3 PRO-219. RX PubMed=10208579; DOI=10.1097/00001756-199902250-00011; RA Smith M.J., Gardner R.J., Knight M.A., Forrest S.M., Beyreuther K., RA Storey E., McLean C.A., Cotton R.G., Cappal R., Masters C.L.; RT "Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of RT the presenilin-1 gene."; RL NeuroReport 10:503-507(1999). RN [88] RP VARIANT AD3 ASN-116. RX PubMed=10439444; DOI=10.1097/00001756-199908020-00006; RA Romero I., Joergensen P., Bolwig G., Fraser P.E., Rogaeva E., Mann D., RA Havsager A.-M., Joergensen A.L.; RT "A presenilin-1 Thr116Asn substitution in a family with early-onset RT Alzheimer's disease."; RL NeuroReport 10:2255-2260(1999). RN [89] RP VARIANTS AD3 VAL-79; LEU-105 AND VAL-139, AND VARIANT GLY-318. RX PubMed=10631141; DOI=10.1086/302702; RA Finckh U., Mueller-Thomsen T., Mann U., Eggers C., Marksteiner J., RA Meins W., Binetti G., Alberici A., Hock C., Nitsch R.M., Gal A.; RT "High prevalence of pathogenic mutations in patients with early-onset RT dementia detected by sequence analyses of four different genes."; RL Am. J. Hum. Genet. 66:110-117(2000). RN [90] RP VARIANT AD3 SER-405. RX PubMed=10644793; DOI=10.1136/jnnp.68.2.220; RA Yasuda M., Maeda S., Kawamata T., Tamaoka A., Yamamoto Y., Kuroda S., RA Maeda K., Tanaka C.; RT "Novel presenilin-1 mutation with widespread cortical amyloid deposition RT but limited cerebral amyloid angiopathy."; RL J. Neurol. Neurosurg. Psych. 68:220-223(2000). RN [91] RP VARIANT AD3 SER-92. RX PubMed=11027672; DOI=10.1006/bbrc.2000.3646; RA Lewis P.A., Perez-Tur J., Golde T.E., Hardy J.; RT "The presenilin 1 C92S mutation increases abeta 42 production."; RL Biochem. Biophys. Res. Commun. 277:261-263(2000). RN [92] RP VARIANT FTD1 PRO-113. RX PubMed=11094121; DOI=10.1212/wnl.55.10.1577; RA Raux G., Gantier R., Thomas-Anterion C., Boulliat J., Verpillat P., RA Hannequin D., Brice A., Frebourg T., Campion D.; RT "Dementia with prominent frontotemporal features associated with L113P RT presenilin 1 mutation."; RL Neurology 55:1577-1578(2000). RN [93] RP VARIANTS AD3 MET-94; THR-143 AND ALA-280, AND VARIANT GLY-318. RX PubMed=11568920; RX DOI=10.1002/1096-8628(20011001)103:2<138::aid-ajmg1529>3.0.co;2-8; RA Arango D., Cruts M., Torres O., Backhovens H., Serrano M.L., Villareal E., RA Montanes P., Matallana D., Cano C., Van Broeckhoven C., Jacquier M.; RT "Systematic genetic study of Alzheimer disease in Latin America: mutation RT frequencies of the amyloid beta precursor protein and presenilin genes in RT Colombia."; RL Am. J. Med. Genet. 103:138-143(2001). RN [94] RP VARIANT AD3 VAL-282, AND CHARACTERIZATION OF VARIANT AD3 VAL-282. RX PubMed=11701593; DOI=10.1093/brain/124.12.2383; RA Dermaut B., Kumar-Singh S., De Jonghe C., Cruts M., Loefgren A., Luebke U., RA Cras P., Dom R., De Deyn P.P., Martin J.J., Van Broeckhoven C.; RT "Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease RT due to a novel presenilin 1 mutation."; RL Brain 124:2383-2392(2001). RN [95] RP ERRATUM OF PUBMED:11701593, AND VARIANT AD3 GLU-431. RA Ringman J.M., Jain V., Murrell J., Ghetti B., Cochran E.J.; RL Hum. Genet. 109:242-242(2001). RN [96] RP VARIANT AD3 ALA-206. RX PubMed=11710891; DOI=10.1001/jama.286.18.2257; RA Athan E.S., Williamson J., Ciappa A., Santana V., Romas S.N., Lee J.H., RA Rondon H., Lantigua R.A., Medrano M., Torres M., Arawaka S., Rogaeva E., RA Song Y.-Q., Sato C., Kawarai T., Fafel K.C., Boss M.A., Seltzer W.K., RA Stern Y., St George-Hyslop P.H., Tycko B., Mayeux R.; RT "A founder mutation in presenilin 1 causing early-onset Alzheimer disease RT in unrelated Caribbean Hispanic families."; RL JAMA 286:2257-2263(2001). RN [97] RP VARIANT AD3 ILE-237. RX PubMed=11561050; DOI=10.1136/jnnp.71.4.556; RA Sodeyama N., Iwata T., Ishikawa K., Mizusawa H., Yamada M., Itoh Y., RA Otomo E., Matsushita M., Komatsuzaki Y.; RT "Very early onset Alzheimer's disease with spastic paraparesis associated RT with a novel presenilin 1 mutation (Phe237Ile)."; RL J. Neurol. Neurosurg. Psych. 71:556-557(2001). RN [98] RP VARIANTS AD3 GLN-35; VAL-79; CYS-115; ASN-116; THR-143; ILE-146; LEU-146; RP VAL-146; TYR-156 DELINS PHE-THR-TYR; ARG-163; LEU-177; SER-177; PRO-178; RP ALA-206; SER-206; GLU-209; LEU-213; ARG-222; THR-231; LEU-233; PRO-235; RP PHE-261; ARG-274; ARG-352 INS; ILE-354; GLN-358; TYR-365; VAL-394; PHE-418; RP GLU-431; PHE-435 AND VAL-439, AND VARIANT GLY-318. RX PubMed=11524469; DOI=10.1212/wnl.57.4.621; RA Rogaeva E.A., Fafel K.C., Song Y.Q., Medeiros H., Sato C., Liang Y., RA Richard E., Rogaev E.I., Frommelt P., Sadovnick A.D., Meschino W., RA Rockwood K., Boss M.A., Mayeux R., St George-Hyslop P.; RT "Screening for PS1 mutations in a referral-based series of AD cases: 21 RT novel mutations."; RL Neurology 57:621-625(2001). RN [99] RP VARIANT AD3 SER-266. RX PubMed=11920851; DOI=10.1002/ajmg.10250; RA Matsubara-Tsutsui M., Yasuda M., Yamagata H., Nomura T., Taguchi K., RA Kohara K., Miyoshi K., Miki T.; RT "Molecular evidence of presenilin 1 mutation in familial early onset RT dementia."; RL Am. J. Med. Genet. 114:292-298(2002). RN [100] RP VARIANT AD3 LEU-89. RX PubMed=11796781; DOI=10.1136/jnnp.72.2.266; RA Queralt R., Ezquerra M., Lleo A., Castellvi M., Gelpi J., Ferrer I., RA Acarin N., Pasarin L., Blesa R., Oliva R.; RT "A novel mutation (V89L) in the presenilin 1 gene in a family with early RT onset Alzheimer's disease and marked behavioural disturbances."; RL J. Neurol. Neurosurg. Psych. 72:266-269(2002). RN [101] RP VARIANT AD3 GLY-280. RX PubMed=12370477; DOI=10.1212/wnl.59.7.1108; RA O'Riordan S., McMonagle P., Janssen J.C., Fox N.C., Farrell M., RA Collinge J., Rossor M.N., Hutchinson M.; RT "Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white- RT matter abnormalities."; RL Neurology 59:1108-1110(2002). RN [102] RP VARIANT AD3 PRO-166. RX PubMed=12048239; DOI=10.1073/pnas.112686799; RA Moehlmann T., Winkler E., Xia X., Edbauer D., Murrell J., Capell A., RA Kaether C., Zheng H., Ghetti B., Haass C., Steiner H.; RT "Presenilin-1 mutations of leucine 166 equally affect the generation of the RT Notch and APP intracellular domains independent of their effect on Abeta 42 RT production."; RL Proc. Natl. Acad. Sci. U.S.A. 99:8025-8030(2002). RN [103] RP VARIANT AD3 MET-174. RX PubMed=12484344; DOI=10.1007/s10048-002-0136-6; RA Bertoli-Avella A.M., Marcheco Teruel B., Llibre Rodriguez J.J., RA Gomez Viera N., Borrajero-Martinez I., Severijnen E.A., Joosse M., RA van Duijn C.M., Heredero Baute L., Heutink P.; RT "A novel presenilin 1 mutation (L174 M) in a large Cuban family with early RT onset Alzheimer disease."; RL Neurogenetics 4:97-104(2002). RN [104] RP VARIANT AD3 VAL-271. RX PubMed=12493737; DOI=10.1074/jbc.m211827200; RA Kwok J.B.J., Halliday G.M., Brooks W.S., Dolios G., Laudon H., Murayama O., RA Hallupp M., Badenhop R.F., Vickers J., Wang R., Naslund J., Takashima A., RA Gandy S.E., Schofield P.R.; RT "Presenilin-1 mutation L271V results in altered exon 8 splicing and RT Alzheimer's disease with non-cored plaques and no neuritic dystrophy."; RL J. Biol. Chem. 278:6748-6754(2003). RN [105] RP VARIANTS AD3 CYS-115; ILE-146; VAL-153; CYS-154; ILE-168 DEL; PRO-171; RP ASP-184; PHE-229; VAL-235; LEU-237; VAL-260; PHE-263; HIS-269; MET-377 AND RP VAL-378, AND VARIANT GLY-318. RX PubMed=12552037; DOI=10.1212/01.wnl.0000042088.22694.e3; RA Janssen J.C., Beck J.A., Campbell T.A., Dickinson A., Fox N.C., RA Harvey R.J., Houlden H., Rossor M.N., Collinge J.; RT "Early onset familial Alzheimer's disease: Mutation frequency in 31 RT families."; RL Neurology 60:235-239(2003). RN [106] RP VARIANT PIDB VAL-183, CHARACTERIZATION OF VARIANTS AD3 THR-143 AND VAL-282, RP AND CHARACTERIZATION OF VARIANT PIDB VAL-183. RX PubMed=15122701; DOI=10.1002/ana.20083; RA Dermaut B., Kumar-Singh S., Engelborghs S., Theuns J., Rademakers R., RA Saerens J., Pickut B.A., Peeters K., van den Broeck M., Vennekens K., RA Claes S., Cruts M., Cras P., Martin J.J., Van Broeckhoven C., De Deyn P.P.; RT "A novel presenilin 1 mutation associated with Pick's disease but not beta- RT amyloid plaques."; RL Ann. Neurol. 55:617-626(2004). RN [107] RP VARIANT AD3 PRO-85, AND CHARACTERIZATION OF VARIANT AD3 PRO-85. RX PubMed=15534188; DOI=10.1001/archneur.61.11.1773; RA Ataka S., Tomiyama T., Takuma H., Yamashita T., Shimada H., Tsutada T., RA Kawabata K., Mori H., Miki T.; RT "A novel presenilin-1 mutation (Leu85Pro) in early-onset Alzheimer disease RT with spastic paraparesis."; RL Arch. Neurol. 61:1773-1776(2004). RN [108] RP VARIANT AD3 ILE-278. RX PubMed=15534260; DOI=10.1212/01.wnl.0000143060.98164.1a; RA Godbolt A.K., Beck J.A., Collinge J., Garrard P., Warren J.D., Fox N.C., RA Rossor M.N.; RT "A presenilin 1 R278I mutation presenting with language impairment."; RL Neurology 63:1702-1704(2004). RN [109] RP VARIANT AD3 ASN-154. RX PubMed=15364419; DOI=10.1016/j.neulet.2004.07.057; RA Hattori S., Sakuma K., Wakutani Y., Wada K., Shimoda M., Urakami K., RA Kowa H., Nakashima K.; RT "A novel presenilin 1 mutation (Y154N) in a patient with early onset RT Alzheimer's disease with spastic paraparesis."; RL Neurosci. Lett. 368:319-322(2004). RN [110] RP VARIANT AD3 PHE-170. RX PubMed=16344340; DOI=10.1001/archneur.62.12.1821; RA Snider B.J., Norton J., Coats M.A., Chakraverty S., Hou C.E., Jervis R., RA Lendon C.L., Goate A.M., McKeel D.W. Jr., Morris J.C.; RT "Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy RT bodies in the third decade of life."; RL Arch. Neurol. 62:1821-1830(2005). RN [111] RP VARIANT AD3 LEU-97. RX PubMed=15851849; DOI=10.3233/jad-2005-7204; RA Jia J., Xu E., Shao Y., Jia J., Sun Y., Li D.; RT "One novel presenilin-1 gene mutation in a Chinese pedigree of familial RT Alzheimer's disease."; RL J. Alzheimers Dis. 7:119-124(2005). RN [112] RP VARIANT CMD1U GLY-333. RX PubMed=17186461; DOI=10.1086/509900; RA Li D., Parks S.B., Kushner J.D., Nauman D., Burgess D., Ludwigsen S., RA Partain J., Nixon R.R., Allen C.N., Irwin R.P., Jakobs P.M., Litt M., RA Hershberger R.E.; RT "Mutations of presenilin genes in dilated cardiomyopathy and heart RT failure."; RL Am. J. Hum. Genet. 79:1030-1039(2006). RN [113] RP CHARACTERIZATION OF VARIANTS AD3 VAL-79; THR-143; VAL-231; PHE-262; RP PHE-263; VAL-282 AND ALA-384. RX PubMed=16752394; DOI=10.1002/humu.20336; RA Kumar-Singh S., Theuns J., Van Broeck B., Pirici D., Vennekens K., RA Corsmit E., Cruts M., Dermaut B., Wang R., Van Broeckhoven C.; RT "Mean age-of-onset of familial alzheimer disease caused by presenilin RT mutations correlates with both increased Abeta42 and decreased Abeta40."; RL Hum. Mutat. 27:686-695(2006). RN [114] RP VARIANT AD3 GLU-431. RX PubMed=16628450; DOI=10.1007/s10048-006-0043-3; RA Yescas P., Huertas-Vazquez A., Villarreal-Molina M.T., Rasmussen A., RA Tusie-Luna M.T., Lopez M., Canizales-Quinteros S., Alonso M.E.; RT "Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing RT early-onset Alzheimer's disease in Mexican families."; RL Neurogenetics 7:195-200(2006). RN [115] RP VARIANT AD3 GLU-431. RX PubMed=16897084; DOI=10.1007/s10048-006-0053-1; RA Murrell J., Ghetti B., Cochran E., Macias-Islas M.A., Medina L., RA Varpetian A., Cummings J.L., Mendez M.F., Kawas C., Chui H., Ringman J.M.; RT "The A431E mutation in PSEN1 causing familial Alzheimer's disease RT originating in Jalisco State, Mexico: an additional fifteen families."; RL Neurogenetics 7:277-279(2006). RN [116] RP VARIANT AD3 VAL-79, AND CHARACTERIZATION OF VARIANT AD3 VAL-79. RX PubMed=17366635; DOI=10.1002/ana.21099; RA Kauwe J.S., Jacquart S., Chakraverty S., Wang J., Mayo K., Fagan A.M., RA Holtzman D.M., Morris J.C., Goate A.M.; RT "Extreme cerebrospinal fluid amyloid beta levels identify family with late- RT onset Alzheimer's disease presenilin 1 mutation."; RL Ann. Neurol. 61:446-453(2007). RN [117] RP VARIANT AD3 PHE-170. RX PubMed=17502474; DOI=10.1001/archneur.64.5.738; RA Piccini A., Zanusso G., Borghi R., Noviello C., Monaco S., Russo R., RA Damonte G., Armirotti A., Gelati M., Giordano R., Zambenedetti P., RA Russo C., Ghetti B., Tabaton M.; RT "Association of a presenilin 1 S170F mutation with a novel Alzheimer RT disease molecular phenotype."; RL Arch. Neurol. 64:738-745(2007). RN [118] RP CHARACTERIZATION OF VARIANTS AD3 LEU-117; LEU-146; GLU-246; VAL-260; RP LEU-264 AND GLY-280, FUNCTION, AND MUTAGENESIS OF ASP-257. RX PubMed=17428795; DOI=10.1074/jbc.m611449200; RA Litterst C., Georgakopoulos A., Shioi J., Ghersi E., Wisniewski T., RA Wang R., Ludwig A., Robakis N.K.; RT "Ligand binding and calcium influx induce distinct ectodomain/gamma- RT secretase-processing pathways of EphB2 receptor."; RL J. Biol. Chem. 282:16155-16163(2007). RN [119] RP VARIANT GLY-318. RX PubMed=18485326; DOI=10.1016/j.ajhg.2008.04.014; RA Cornier A.S., Staehling-Hampton K., Delventhal K.M., Saga Y., Caubet J.-F., RA Sasaki N., Ellard S., Young E., Ramirez N., Carlo S.E., Torres J., RA Emans J.B., Turnpenny P.D., Pourquie O.; RT "Mutations in the MESP2 gene cause spondylothoracic dysostosis/Jarcho-Levin RT syndrome."; RL Am. J. Hum. Genet. 82:1334-1341(2008). RN [120] RP CHARACTERIZATION OF VARIANT AD3 THR-213. RX PubMed=18430735; DOI=10.1074/jbc.m801279200; RA Shimojo M., Sahara N., Mizoroki T., Funamoto S., Morishima-Kawashima M., RA Kudo T., Takeda M., Ihara Y., Ichinose H., Takashima A.; RT "Enzymatic characteristics of I213T mutant presenilin-1/gamma-secretase in RT cell models and knock-in mouse brains: familial Alzheimer disease-linked RT mutation impairs gamma-site cleavage of amyloid precursor protein C- RT terminal fragment beta."; RL J. Biol. Chem. 283:16488-16496(2008). RN [121] RP VARIANT AD3 VAL-381. RX PubMed=19797784; DOI=10.1177/1533317509341464; RA Dintchov Traykov L., Mehrabian S., Van den Broeck M., RA Radoslavova Raycheva M., Cruts M., Kirilova Jordanova A., RA Van Broeckhoven C.; RT "Novel PSEN1 mutation in a Bulgarian patient with very early-onset RT Alzheimer's disease, spastic paraparesis, and extrapyramidal signs."; RL Am. J. Alzheimers Dis. Other Demen. 24:404-407(2009). RN [122] RP VARIANT AD3 ARG-217, AND CHARACTERIZATION OF VARIANT AD3 ARG-217. RX PubMed=19667325; DOI=10.1212/wnl.0b013e3181b163ba; RA Norton J.B., Cairns N.J., Chakraverty S., Wang J., Levitch D., Galvin J.E., RA Goate A.; RT "Presenilin1 G217R mutation linked to Alzheimer disease with cotton wool RT plaques."; RL Neurology 73:480-482(2009). RN [123] RP VARIANT AD3 LEU-146. RX PubMed=20164095; DOI=10.1212/wnl.0b013e3181d52785; RA Bruni A.C., Bernardi L., Colao R., Rubino E., Smirne N., Frangipane F., RA Terni B., Curcio S.A., Mirabelli M., Clodomiro A., Di Lorenzo R., RA Maletta R., Anfossi M., Gallo M., Geracitano S., Tomaino C., Muraca M.G., RA Leotta A., Lio S.G., Pinessi L., Rainero I., Sorbi S., Nee L., Milan G., RA Pappata S., Postiglione A., Abbamondi N., Forloni G., St George Hyslop P., RA Rogaeva E., Bugiani O., Giaccone G., Foncin J.F., Spillantini M.G., RA Puccio G.; RT "Worldwide distribution of PSEN1 Met146Leu mutation: a large variability RT for a founder mutation."; RL Neurology 74:798-806(2010). RN [124] RP VARIANT AD3 PHE-435, CHARACTERIZATION OF VARIANTS AD3 PHE-435; GLN-436 AND RP SER-436, MUTAGENESIS OF PRO-433 AND LEU-435, AND FUNCTION. RX PubMed=20460383; DOI=10.1074/jbc.m110.116962; RA Heilig E.A., Xia W., Shen J., Kelleher R.J. III; RT "A presenilin-1 mutation identified in familial Alzheimer disease with RT cotton wool plaques causes a nearly complete loss of gamma-secretase RT activity."; RL J. Biol. Chem. 285:22350-22359(2010). RN [125] RP VARIANT AD3 ASP-206. RX PubMed=21335660; DOI=10.3233/jad-2011-102031; RA Wu Y.Y., Cheng I.H., Lee C.C., Chiu M.J., Lee M.J., Chen T.F., Hsu J.L.; RT "Clinical phenotype of G206D mutation in the presenilin 1 gene in RT pathologically confirmed familial Alzheimer's disease."; RL J. Alzheimers Dis. 25:145-150(2011). RN [126] RP VARIANT CYS-315. RX PubMed=21248752; DOI=10.1038/nature09639; RA Varela I., Tarpey P., Raine K., Huang D., Ong C.K., Stephens P., Davies H., RA Jones D., Lin M.L., Teague J., Bignell G., Butler A., Cho J., RA Dalgliesh G.L., Galappaththige D., Greenman C., Hardy C., Jia M., RA Latimer C., Lau K.W., Marshall J., McLaren S., Menzies A., Mudie L., RA Stebbings L., Largaespada D.A., Wessels L.F.A., Richard S., Kahnoski R.J., RA Anema J., Tuveson D.A., Perez-Mancera P.A., Mustonen V., Fischer A., RA Adams D.J., Rust A., Chan-On W., Subimerb C., Dykema K., Furge K., RA Campbell P.J., Teh B.T., Stratton M.R., Futreal P.A.; RT "Exome sequencing identifies frequent mutation of the SWI/SNF complex gene RT PBRM1 in renal carcinoma."; RL Nature 469:539-542(2011). RN [127] RP VARIANT AD3 ARG-235. RX PubMed=21501661; DOI=10.1016/j.neulet.2011.03.084; RA Antonell A., Balasa M., Oliva R., Llado A., Bosch B., Fabregat N., RA Fortea J., Molinuevo J.L., Sanchez-Valle R.; RT "A novel PSEN1 gene mutation (L235R) associated with familial early-onset RT Alzheimer's disease."; RL Neurosci. Lett. 496:40-42(2011). RN [128] RP CHARACTERIZATION OF VARIANTS AD3 LEU-146; ARG-163 AND ALA-280. RX PubMed=22461631; DOI=10.1074/jbc.m111.300483; RA Chau D.M., Crump C.J., Villa J.C., Scheinberg D.A., Li Y.M.; RT "Familial Alzheimer disease presenilin-1 mutations alter the active site RT conformation of gamma-secretase."; RL J. Biol. Chem. 287:17288-17296(2012). RN [129] RP VARIANTS AD3 ARG-134; ARG-163 AND VAL-262, AND VARIANT TYR-214. RX PubMed=22503161; DOI=10.1016/j.neurobiolaging.2012.02.020; RA Lohmann E., Guerreiro R.J., Erginel-Unaltuna N., Gurunlian N., Bilgic B., RA Gurvit H., Hanagasi H.A., Luu N., Emre M., Singleton A.; RT "Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish RT dementia patients."; RL Neurobiol. Aging 33:1850.E17-1850.E27(2012). RN [130] RP VARIANT AD3 PHE-159. RX PubMed=23123781; DOI=10.1016/j.neulet.2012.10.037; RA Kerchner G.A., Holbrook K.; RT "Novel presenilin-1 Y159F sequence variant associated with early-onset RT Alzheimer's disease."; RL Neurosci. Lett. 531:142-144(2012). RN [131] RP CHARACTERIZATION OF VARIANTS AD3 PRO-166 AND GLN-436, AND MUTAGENESIS OF RP ASP-257 AND ASP-385. RX PubMed=22529981; DOI=10.1371/journal.pone.0035133; RA Cacquevel M., Aeschbach L., Houacine J., Fraering P.C.; RT "Alzheimer's disease-linked mutations in presenilin-1 result in a drastic RT loss of activity in purified gamma-secretase complexes."; RL PLoS ONE 7:E35133-E35133(2012). RN [132] RP CHARACTERIZATION OF VARIANTS AD3 PRO-166; ILE-278; ALA-384; VAL-392; RP TYR-410 AND PHE-435. RX PubMed=23843529; DOI=10.1523/jneurosci.0954-13.2013; RA Heilig E.A., Gutti U., Tai T., Shen J., Kelleher R.J. III; RT "Trans-dominant negative effects of pathogenic PSEN1 mutations on gamma- RT secretase activity and Abeta production."; RL J. Neurosci. 33:11606-11617(2013). RN [133] RP VARIANT AD3 PHE-381. RX PubMed=24121961; DOI=10.3233/jad-131340; RA Dolzhanskaya N., Gonzalez M.A., Sperziani F., Stefl S., Messing J., RA Wen G.Y., Alexov E., Zuchner S., Velinov M.; RT "A novel p.Leu(381)Phe mutation in presenilin 1 is associated with very RT early onset and unusually fast progressing dementia as well as lysosomal RT inclusions typically seen in Kufs disease."; RL J. Alzheimers Dis. 39:23-27(2014). RN [134] RP VARIANT AD3 VAL-153. RX PubMed=24495933; DOI=10.1016/j.neulet.2014.01.016; RA Cornejo-Olivas M.R., Yu C.E., Mazzetti P., Mata I.F., Meza M., RA Lindo-Samanamud S., Leverenz J.B., Bird T.D.; RT "Clinical and molecular studies reveal a PSEN1 mutation (L153V) in a RT Peruvian family with early-onset Alzheimer's disease."; RL Neurosci. Lett. 563:140-143(2014). RN [135] RP VARIANT AD3 VAL-275. RX PubMed=24582897; DOI=10.1016/j.neulet.2014.02.034; RA Luedecke D., Becktepe J.S., Lehmbeck J.T., Finckh U., Yamamoto R., Jahn H., RA Boelmans K.; RT "A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial RT Alzheimer disease."; RL Neurosci. Lett. 566:115-119(2014). RN [136] RP VARIANT AD3 THR-83. RX PubMed=26145164; DOI=10.1016/j.neurobiolaging.2015.06.007; RA Achouri-Rassas A., Ben Ali N., Fray S., Hadj Fredj S., Kechaou M., RA Zakraoui N.O., Cherif A., Chabbi S., Anane N., Messaoud T., Gouider R., RA Belal S.; RT "Novel presenilin 1 mutation (p.I83T) in Tunisian family with early-onset RT Alzheimer's disease."; RL Neurobiol. Aging 36:2904.E09-2904.E11(2015). RN [137] RP VARIANTS AD3 ALA-206 AND VAL-378. RX PubMed=27073747; RA Ravenscroft T.A., Pottier C., Murray M.E., Baker M., Christopher E., RA Levitch D., Brown P.H., Barker W., Duara R., Greig-Custo M., Betancourt A., RA English M., Sun X., Ertekin-Taner N., Graff-Radford N.R., Dickson D.W., RA Rademakers R.; RT "The presenilin 1 p.Gly206Ala mutation is a frequent cause of early-onset RT Alzheimer's disease in Hispanics in Florida."; RL Am. J. Neurodegener. Dis. 5:94-101(2016). RN [138] RP VARIANT AD3 THR-408. RX PubMed=26549787; DOI=10.1016/j.neulet.2015.11.004; RA Tedde A., Bartoli A., Piaceri I., Ferrara S., Bagnoli S., Serio A., RA Sorbi S., Nacmias B.; RT "Novel presenilin 1 mutation (Ile408Thr) in an Italian family with late- RT onset Alzheimer's disease."; RL Neurosci. Lett. 610:150-153(2016). RN [139] RP VARIANT ARG-311, CHARACTERIZATION OF VARIANTS ALA-280 AND ARG-311, AND RP FUNCTION. RX PubMed=28269784; DOI=10.3233/jad-161188; RA Dong J., Qin W., Wei C., Tang Y., Wang Q., Jia J.; RT "A novel PSEN1 K311R mutation discovered in Chinese families with late- RT onset Alzheimer's disease affects amyloid-beta production and tau RT phosphorylation."; RL J. Alzheimers Dis. 57:613-623(2017). RN [140] RP CHARACTERIZATION OF VARIANTS AD3 GLN-35; VAL-79; LEU-82; PRO-85; LEU-89; RP SER-92; MET-94; PHE-96; LEU-97; HIS-115; ASN-116; ASP-120; LYS-120; RP ARG-134; ASP-135; VAL-139; THR-143; LEU-146; ILE-147; VAL-153; ASN-154; RP ARG-163; TYR-163; PRO-166; PRO-169; PHE-170; PRO-171; TRP-173; MET-174; RP LEU-177; PRO-178; VAL-183; ASP-184; ALA-206; SER-206; ARG-209; VAL-209; RP LEU-213; ARG-217; ARG-222; PHE-229; THR-231; LEU-233; THR-233; ARG-235; RP PRO-235; VAL-235; ILE-237; GLU-246; SER-250; VAL-260; PHE-261; PHE-262; RP ARG-263; LEU-264; SER-266; SER-267; GLY-269; VAL-271; ARG-274; VAL-275; RP ALA-280; GLY-280; ARG-282; VAL-285; VAL-286; ILE-354; GLN-358; GLU-378; RP VAL-378; VAL-381; ALA-384; ILE-390; VAL-392; VAL-394; THR-396; SER-405; RP THR-409; TYR-410; PHE-418; PRO-426; GLU-431; PHE-435; SER-436 AND VAL-439, RP CHARACTERIZATION OF VARIANT CMD1U GLY-333, AND MUTAGENESIS OF THR-99; RP PHE-105; ARG-108; LEU-113; PRO-117; GLU-123; HIS-131; ALA-136; ILE-143; RP LEU-150; TRP-165; ILE-168; PHE-176; GLU-184; ILE-202; SER-212; HIS-214; RP LEU-219; GLN-223; LEU-226; SER-230; ILE-238; LYS-239; THR-245; LEU-248; RP TYR-256; VAL-272; GLU-273; ARG-278; PRO-284; THR-291; ARG-352; SER-365; RP ARG-377; PHE-386; VAL-391; VAL-412; LEU-420; LEU-424; ALA-434 AND ILE-437. RX PubMed=27930341; DOI=10.1073/pnas.1618657114; RA Sun L., Zhou R., Yang G., Shi Y.; RT "Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro RT production of Abeta42 and Abeta40 peptides by gamma-secretase."; RL Proc. Natl. Acad. Sci. U.S.A. 114:E476-E485(2017). RN [141] RP VARIANT AD3 ILE-116. RX PubMed=30200536; DOI=10.3390/ijms19092604; RA Bagyinszky E., Lee H.M., Van Giau V., Koh S.B., Jeong J.H., An S.S.A., RA Kim S.; RT "PSEN1 p.Thr116Ile variant in two Korean families with young onset RT Alzheimer's disease."; RL Int. J. Mol. Sci. 19:0-0(2018). RN [142] RP VARIANT AD3 ASN-116. RX PubMed=29404783; DOI=10.1007/s00702-018-1850-z; RA Sutovsky S., Smolek T., Turcani P., Petrovic R., Brandoburova P., RA Jadhav S., Novak P., Attems J., Zilka N.; RT "Neuropathology and biochemistry of early onset familial Alzheimer's RT disease caused by presenilin-1 missense mutation Thr116Asn."; RL J. Neural Transm. 125:965-976(2018). RN [143] RP VARIANTS AD3 PHE-142 AND ASP-206. RX PubMed=29175279; DOI=10.1016/j.neurobiolaging.2017.10.011; RA Wang J.C., Alinaghi S., Tafakhori A., Sikora E., Azcona L.J., RA Karkheiran S., Goate A., Paisan-Ruiz C., Darvish H.; RT "Genetic screening in two Iranian families with early-onset Alzheimer's RT disease identified a novel PSEN1 mutation."; RL Neurobiol. Aging 62:E15-E17(2018). RN [144] RP VARIANT AD3 ALA-417. RX PubMed=30180983; DOI=10.1016/j.neurobiolaging.2018.08.003; RA Giau V.V., Wang M.J., Bagyinszky E., Youn Y.C., An S.S.A., Kim S.; RT "Novel PSEN1 p.Gly417Ala mutation in a Korean patient with early-onset RT Alzheimer's disease with parkinsonism."; RL Neurobiol. Aging 72:E13-E17(2018). RN [145] RP VARIANT AD3 PHE-170. RX PubMed=29466804; DOI=10.1159/000485899; RA Tiedt H.O., Benjamin B., Niedeggen M., Lueschow A.; RT "Phenotypic variability in autosomal dominant familial Alzheimer disease RT due to the S170F mutation of presenilin-1."; RL Neurodegener. Dis. 18:57-68(2018). CC -!- FUNCTION: Catalytic subunit of the gamma-secretase complex, an CC endoprotease complex that catalyzes the intramembrane cleavage of CC integral membrane proteins such as Notch receptors and APP (amyloid- CC beta precursor protein) (PubMed:10206644, PubMed:10545183, CC PubMed:10593990, PubMed:10811883, PubMed:10899933, PubMed:12679784, CC PubMed:12740439, PubMed:15274632, PubMed:20460383, PubMed:25043039, CC PubMed:26280335, PubMed:28269784, PubMed:30598546, PubMed:30630874). CC Requires the presence of the other members of the gamma-secretase CC complex for protease activity (PubMed:15274632, PubMed:25043039, CC PubMed:26280335, PubMed:30598546, PubMed:30630874). Plays a role in CC Notch and Wnt signaling cascades and regulation of downstream processes CC via its role in processing key regulatory proteins, and by regulating CC cytosolic CTNNB1 levels (PubMed:10593990, PubMed:10811883, CC PubMed:10899933, PubMed:9738936). Stimulates cell-cell adhesion via its CC interaction with CDH1; this stabilizes the complexes between CDH1 (E- CC cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 CC and JUP (gamma-catenin) (PubMed:11953314). Under conditions of CC apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314). This CC promotes the disassembly of the complexes between CDH1 and CTNND1, JUP CC and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby CC negatively regulates Wnt signaling (PubMed:11953314, PubMed:9738936). CC Required for normal embryonic brain and skeleton development, and for CC normal angiogenesis (By similarity). Mediates the proteolytic cleavage CC of EphB2/CTF1 into EphB2/CTF2 (PubMed:17428795, PubMed:28269784). The CC holoprotein functions as a calcium-leak channel that allows the passive CC movement of calcium from endoplasmic reticulum to cytosol and is CC therefore involved in calcium homeostasis (PubMed:16959576, CC PubMed:25394380). Involved in the regulation of neurite outgrowth CC (PubMed:15004326, PubMed:20460383). Is a regulator of presynaptic CC facilitation, spike transmission and synaptic vesicles replenishment in CC a process that depends on gamma-secretase activity. It acts through the CC control of SYT7 presynaptic expression (By similarity). CC {ECO:0000250|UniProtKB:P49769, ECO:0000269|PubMed:10206644, CC ECO:0000269|PubMed:10545183, ECO:0000269|PubMed:10593990, CC ECO:0000269|PubMed:10811883, ECO:0000269|PubMed:10899933, CC ECO:0000269|PubMed:11953314, ECO:0000269|PubMed:12679784, CC ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:15004326, CC ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:15341515, CC ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:16959576, CC ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:20460383, CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25394380, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:28269784, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, CC ECO:0000269|PubMed:9738936}. CC -!- SUBUNIT: Homodimer. The functional gamma-secretase complex is composed CC of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), CC nicastrin (NCSTN), APH1 (APH1A/APH1B) and PEN2 (PubMed:12679784, CC PubMed:12740439, PubMed:15274632, PubMed:25043039, PubMed:25394380, CC PubMed:26280335, PubMed:30598546, PubMed:30630874). Such minimal CC complex is sufficient for secretase activity (PubMed:12679784, CC PubMed:12740439, PubMed:15274632, PubMed:25043039, PubMed:26280335, CC PubMed:30598546, PubMed:30630874). Other components which are CC associated with the complex include SLC25A64, SLC5A7, PHB and PSEN1 CC isoform 3. As part of the gamma-secretase complex, interacts with CRB2 CC (via transmembrane domain) (PubMed:20299451). Predominantly heterodimer CC of a N-terminal (NTF) and a C-terminal (CTF) endoproteolytical fragment CC (PubMed:15274632). Associates with proteolytic processed C-terminal CC fragments C83 and C99 of the amyloid precursor protein (APP) (via CC transmembrane domain) (PubMed:30630874). Associates with NOTCH1 (via CC transmembrane domain) (PubMed:10593990, PubMed:30598546). Associates CC with cadherin/catenin adhesion complexes through direct binding to CDH1 CC or CDH2 (PubMed:11953314, PubMed:14515347, PubMed:16126725). CC Interaction with CDH1 stabilizes the complex and stimulates cell-cell CC aggregation (PubMed:11953314). Interaction with CDH2 is essential for CC trafficking of CDH2 from the endoplasmic reticulum to the plasma CC membrane (PubMed:14515347). Interacts with CTNND2, CTNNB1, CTNND1, JUP, CC HERPUD1, FLNA, FLNB, MTCH1, PKP4 and PARL (PubMed:10037471, CC PubMed:10551805, PubMed:11799129, PubMed:11953314, PubMed:12214059, CC PubMed:16126725, PubMed:9437013, PubMed:9738936). Interacts through its CC N-terminus with GFAP (isoform 2) (PubMed:12058025). Interacts with CC DOCK3; this interaction mediates the membrane association of DOCK3 CC (PubMed:10854253). Interacts with isoform 1 and isoform 3 of UBQLN1 CC (PubMed:21143716). {ECO:0000250|UniProtKB:P49769, CC ECO:0000269|PubMed:10037471, ECO:0000269|PubMed:10551805, CC ECO:0000269|PubMed:10854253, ECO:0000269|PubMed:11799129, CC ECO:0000269|PubMed:11953314, ECO:0000269|PubMed:12058025, CC ECO:0000269|PubMed:12214059, ECO:0000269|PubMed:12679784, CC ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:14515347, CC ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:16126725, CC ECO:0000269|PubMed:20299451, ECO:0000269|PubMed:21143716, CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25394380, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:30598546, CC ECO:0000269|PubMed:30630874, ECO:0000269|PubMed:9437013, CC ECO:0000269|PubMed:9738936}. CC -!- INTERACTION: CC P49768; Q02410: APBA1; NbExp=4; IntAct=EBI-297277, EBI-368690; CC P49768; Q96BI3: APH1A; NbExp=3; IntAct=EBI-297277, EBI-2606935; CC P49768; P05067: APP; NbExp=6; IntAct=EBI-297277, EBI-77613; CC P49768; P05067-4: APP; NbExp=4; IntAct=EBI-297277, EBI-302641; CC P49768; P56817: BACE1; NbExp=6; IntAct=EBI-297277, EBI-2433139; CC P49768; Q16543: CDC37; NbExp=3; IntAct=EBI-297277, EBI-295634; CC P49768; P12830: CDH1; NbExp=2; IntAct=EBI-297277, EBI-727477; CC P49768; Q9BQ95: ECSIT; NbExp=4; IntAct=EBI-297277, EBI-712452; CC P49768; P21333: FLNA; NbExp=2; IntAct=EBI-297277, EBI-350432; CC P49768; O75369: FLNB; NbExp=2; IntAct=EBI-297277, EBI-352089; CC P49768; Q92542: NCSTN; NbExp=6; IntAct=EBI-297277, EBI-998440; CC P49768; Q99569: PKP4; NbExp=3; IntAct=EBI-297277, EBI-726447; CC P49768; Q9NZ42: PSENEN; NbExp=4; IntAct=EBI-297277, EBI-998468; CC P49768; P50502: ST13; NbExp=3; IntAct=EBI-297277, EBI-357285; CC P49768; P55061: TMBIM6; NbExp=12; IntAct=EBI-297277, EBI-1045825; CC P49768; P49755: TMED10; NbExp=4; IntAct=EBI-297277, EBI-998422; CC P49768; Q9NZC2: TREM2; NbExp=5; IntAct=EBI-297277, EBI-14036387; CC P49768; Q9UMX0: UBQLN1; NbExp=3; IntAct=EBI-297277, EBI-741480; CC P49768; O35430: Apba1; Xeno; NbExp=2; IntAct=EBI-297277, EBI-704760; CC P49768; P98084: Apba2; Xeno; NbExp=2; IntAct=EBI-297277, EBI-81669; CC P49768; P62493: RAB11A; Xeno; NbExp=2; IntAct=EBI-297277, EBI-7030357; CC P49768-2; P63010-2: AP2B1; NbExp=6; IntAct=EBI-11047108, EBI-11529439; CC P49768-2; P05067: APP; NbExp=6; IntAct=EBI-11047108, EBI-77613; CC P49768-2; P16870: CPE; NbExp=3; IntAct=EBI-11047108, EBI-711320; CC P49768-2; Q5D0E6-2: DALRD3; NbExp=3; IntAct=EBI-11047108, EBI-9090939; CC P49768-2; Q9H816: DCLRE1B; NbExp=3; IntAct=EBI-11047108, EBI-3508943; CC P49768-2; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-11047108, EBI-396453; CC P49768-2; Q06787-7: FMR1; NbExp=3; IntAct=EBI-11047108, EBI-25856644; CC P49768-2; P02792: FTL; NbExp=3; IntAct=EBI-11047108, EBI-713279; CC P49768-2; P68431: H3C12; NbExp=6; IntAct=EBI-11047108, EBI-79722; CC P49768-2; Q12891: HYAL2; NbExp=3; IntAct=EBI-11047108, EBI-2806068; CC P49768-2; Q6DN90-2: IQSEC1; NbExp=6; IntAct=EBI-11047108, EBI-21911304; CC P49768-2; Q9NVX7-2: KBTBD4; NbExp=3; IntAct=EBI-11047108, EBI-25871195; CC P49768-2; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-11047108, EBI-1044640; CC P49768-2; Q9BYZ2: LDHAL6B; NbExp=6; IntAct=EBI-11047108, EBI-1108377; CC P49768-2; Q8TDB4: MGARP; NbExp=6; IntAct=EBI-11047108, EBI-4397720; CC P49768-2; A4FUJ8: MKL1; NbExp=6; IntAct=EBI-11047108, EBI-21250407; CC P49768-2; Q9Y605: MRFAP1; NbExp=3; IntAct=EBI-11047108, EBI-995714; CC P49768-2; Q86WS3: OOSP2; NbExp=3; IntAct=EBI-11047108, EBI-25888682; CC P49768-2; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-11047108, EBI-1058491; CC P49768-2; Q13113: PDZK1IP1; NbExp=6; IntAct=EBI-11047108, EBI-716063; CC P49768-2; P53350: PLK1; NbExp=3; IntAct=EBI-11047108, EBI-476768; CC P49768-2; O14494: PLPP1; NbExp=3; IntAct=EBI-11047108, EBI-2865290; CC P49768-2; Q9NZ42: PSENEN; NbExp=3; IntAct=EBI-11047108, EBI-998468; CC P49768-2; Q6ZNA4-2: RNF111; NbExp=6; IntAct=EBI-11047108, EBI-21535400; CC P49768-2; Q9ULX5: RNF112; NbExp=6; IntAct=EBI-11047108, EBI-25829984; CC P49768-2; Q8N488: RYBP; NbExp=6; IntAct=EBI-11047108, EBI-752324; CC P49768-2; Q2NKQ1-4: SGSM1; NbExp=3; IntAct=EBI-11047108, EBI-10182463; CC P49768-2; Q9GZS3: SKIC8; NbExp=6; IntAct=EBI-11047108, EBI-358545; CC P49768-2; Q3KNW5: SLC10A6; NbExp=3; IntAct=EBI-11047108, EBI-18159983; CC P49768-2; Q99932-2: SPAG8; NbExp=6; IntAct=EBI-11047108, EBI-11959123; CC P49768-2; O00300: TNFRSF11B; NbExp=3; IntAct=EBI-11047108, EBI-15481185; CC P49768-2; Q96NC0: ZMAT2; NbExp=6; IntAct=EBI-11047108, EBI-2682299; CC PRO_0000025591; Q63053: Arc; Xeno; NbExp=3; IntAct=EBI-2606326, EBI-5275794; CC PRO_0000025592; P35613: BSG; NbExp=6; IntAct=EBI-2606356, EBI-750709; CC PRO_0000025592; Q92542: NCSTN; NbExp=2; IntAct=EBI-2606356, EBI-998440; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum CC {ECO:0000269|PubMed:25394380}. Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:8574969, CC ECO:0000269|PubMed:9738936, ECO:0000305|PubMed:10037471, CC ECO:0000305|PubMed:15274632}; Multi-pass membrane protein CC {ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25918421, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26623517, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Golgi CC apparatus membrane {ECO:0000269|PubMed:10593990, CC ECO:0000269|PubMed:8574969, ECO:0000305|PubMed:10037471, CC ECO:0000305|PubMed:15274632}; Multi-pass membrane protein CC {ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25918421, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26623517, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Cytoplasmic CC granule {ECO:0000269|PubMed:11987239}. Cell membrane CC {ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:11953314, CC ECO:0000269|PubMed:11987239, ECO:0000269|PubMed:21143716}; Multi-pass CC membrane protein {ECO:0000269|PubMed:25918421, CC ECO:0000269|PubMed:26623517, ECO:0000269|PubMed:30598546, CC ECO:0000269|PubMed:30630874}. Cell projection, growth cone CC {ECO:0000269|PubMed:15004326}. Early endosome CC {ECO:0000269|PubMed:25394380}. Early endosome membrane CC {ECO:0000305|PubMed:25394380}; Multi-pass membrane protein CC {ECO:0000269|PubMed:25918421, ECO:0000269|PubMed:26623517, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Cell CC projection, neuron projection {ECO:0000269|PubMed:15004326}. Cell CC projection, axon {ECO:0000250|UniProtKB:Q4JIM4}. Synapse CC {ECO:0000250|UniProtKB:Q4JIM4}. Note=Translocates with bound NOTCH1 CC from the endoplasmic reticulum and/or Golgi to the cell surface CC (PubMed:10593990). Colocalizes with CDH1/2 at sites of cell-cell CC contact. Colocalizes with CTNNB1 in the endoplasmic reticulum and the CC proximity of the plasma membrane (PubMed:9738936). Also present in CC azurophil granules of neutrophils (PubMed:11987239). Colocalizes with CC UBQLN1 in the cell membrane and in cytoplasmic juxtanuclear structures CC called aggresomes (PubMed:21143716). Also highly enriched in CC mitochondria-associated endoplasmic reticulum membrane contact site (By CC similarity). {ECO:0000250|UniProtKB:P49769, CC ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:11987239, CC ECO:0000269|PubMed:21143716, ECO:0000269|PubMed:9738936}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=7; CC Name=1; Synonyms=I-467; CC IsoId=P49768-1; Sequence=Displayed; CC Name=2; Synonyms=I-463; CC IsoId=P49768-2; Sequence=VSP_005191; CC Name=3; Synonyms=I-374; CC IsoId=P49768-3; Sequence=VSP_005191, VSP_005192; CC Name=4; Synonyms=Minilin; CC IsoId=P49768-4; Sequence=VSP_007986, VSP_007987; CC Name=5; CC IsoId=P49768-5; Sequence=VSP_005192; CC Name=6; CC IsoId=P49768-6; Sequence=VSP_012288; CC Name=7; CC IsoId=P49768-7; Sequence=VSP_041440; CC -!- TISSUE SPECIFICITY: Detected in azurophile granules in neutrophils and CC in platelet cytoplasmic granules (at protein level) (PubMed:11987239). CC Expressed in a wide range of tissues including various regions of the CC brain, liver, spleen and lymph nodes (PubMed:7596406, PubMed:8574969, CC PubMed:8641442). {ECO:0000269|PubMed:11987239, CC ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:8574969, CC ECO:0000269|PubMed:8641442}. CC -!- DOMAIN: The PAL motif is required for normal active site conformation. CC {ECO:0000269|PubMed:16305624}. CC -!- DOMAIN: Substrates, such as NOTCH1 and APP peptides, are bound between CC PSEN1 transmembrane domains and via the first lumenal loop and the CC cytoplasmic loop between the sixth and seventh transmembrane domains. CC Substrate binding causes a conformation change and formation of an CC intermolecular antiparallel beta-sheet between PSEN1 and its CC substrates. {ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. CC -!- PTM: Heterogeneous proteolytic processing generates N-terminal (NTF) CC and C-terminal (CTF) fragments of approximately 35 and 20 kDa, CC respectively. During apoptosis, the C-terminal fragment (CTF) is CC further cleaved by caspase-3 to produce the fragment, PS1-CTF12. CC {ECO:0000269|PubMed:10545183, ECO:0000269|PubMed:15274632, CC ECO:0000269|PubMed:9173929, ECO:0000269|PubMed:9485372}. CC -!- PTM: After endoproteolysis, the C-terminal fragment (CTF) is CC phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on CC Ser-346 inhibits endoproteolysis. {ECO:0000269|PubMed:14576165, CC ECO:0000269|PubMed:9144240}. CC -!- DISEASE: Alzheimer disease 3 (AD3) [MIM:607822]: A familial early-onset CC form of Alzheimer disease. Alzheimer disease is a neurodegenerative CC disorder characterized by progressive dementia, loss of cognitive CC abilities, and deposition of fibrillar amyloid proteins as CC intraneuronal neurofibrillary tangles, extracellular amyloid plaques CC and vascular amyloid deposits. The major constituents of these plaques CC are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, CC that are produced by the proteolysis of the transmembrane APP protein. CC The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved CC products, such as C31, are also implicated in neuronal death. CC {ECO:0000269|PubMed:10025789, ECO:0000269|PubMed:10090481, CC ECO:0000269|PubMed:10200054, ECO:0000269|PubMed:10208579, CC ECO:0000269|PubMed:10439444, ECO:0000269|PubMed:10441572, CC ECO:0000269|PubMed:10447269, ECO:0000269|PubMed:10533070, CC ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10644793, CC ECO:0000269|PubMed:11027672, ECO:0000269|PubMed:11524469, CC ECO:0000269|PubMed:11561050, ECO:0000269|PubMed:11568920, CC ECO:0000269|PubMed:11701593, ECO:0000269|PubMed:11710891, CC ECO:0000269|PubMed:11796781, ECO:0000269|PubMed:11920851, CC ECO:0000269|PubMed:12048239, ECO:0000269|PubMed:12058025, CC ECO:0000269|PubMed:12370477, ECO:0000269|PubMed:12484344, CC ECO:0000269|PubMed:12493737, ECO:0000269|PubMed:12552037, CC ECO:0000269|PubMed:15004326, ECO:0000269|PubMed:15122701, CC ECO:0000269|PubMed:15364419, ECO:0000269|PubMed:15534188, CC ECO:0000269|PubMed:15534260, ECO:0000269|PubMed:15851849, CC ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:16344340, CC ECO:0000269|PubMed:16628450, ECO:0000269|PubMed:16752394, CC ECO:0000269|PubMed:16897084, ECO:0000269|PubMed:16959576, CC ECO:0000269|PubMed:17366635, ECO:0000269|PubMed:17428795, CC ECO:0000269|PubMed:17502474, ECO:0000269|PubMed:18430735, CC ECO:0000269|PubMed:19667325, ECO:0000269|PubMed:19797784, CC ECO:0000269|PubMed:20164095, ECO:0000269|PubMed:20460383, CC ECO:0000269|PubMed:21335660, ECO:0000269|PubMed:21501661, CC ECO:0000269|PubMed:22461631, ECO:0000269|PubMed:22503161, CC ECO:0000269|PubMed:22529981, ECO:0000269|PubMed:23123781, CC ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:24121961, CC ECO:0000269|PubMed:24495933, ECO:0000269|PubMed:24582897, CC ECO:0000269|PubMed:25394380, ECO:0000269|PubMed:26145164, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26549787, CC ECO:0000269|PubMed:27073747, ECO:0000269|PubMed:27930341, CC ECO:0000269|PubMed:29175279, ECO:0000269|PubMed:29404783, CC ECO:0000269|PubMed:29466804, ECO:0000269|PubMed:30180983, CC ECO:0000269|PubMed:30200536, ECO:0000269|PubMed:7550356, CC ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:7651536, CC ECO:0000269|PubMed:8634711, ECO:0000269|PubMed:8634712, CC ECO:0000269|PubMed:8733303, ECO:0000269|PubMed:8837617, CC ECO:0000269|PubMed:8875251, ECO:0000269|PubMed:9172170, CC ECO:0000269|PubMed:9225696, ECO:0000269|PubMed:9298817, CC ECO:0000269|PubMed:9384602, ECO:0000269|PubMed:9507958, CC ECO:0000269|PubMed:9521423, ECO:0000269|PubMed:9719376, CC ECO:0000269|PubMed:9831473, ECO:0000269|PubMed:9833068, CC ECO:0000269|Ref.95}. Note=The disease is caused by variants affecting CC the gene represented in this entry. CC -!- DISEASE: Frontotemporal dementia 1 (FTD1) [MIM:600274]: A form of CC dementia characterized by pathologic finding of frontotemporal lobar CC degeneration, presenile dementia with behavioral changes, deterioration CC of cognitive capacities and loss of memory. In some cases, parkinsonian CC symptoms are prominent. Neuropathological changes include CC frontotemporal atrophy often associated with atrophy of the basal CC ganglia, substantia nigra, amygdala. In most cases, protein tau CC deposits are found in glial cells and/or neurons. CC {ECO:0000269|PubMed:11094121}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Cardiomyopathy, dilated, 1U (CMD1U) [MIM:613694]: A disorder CC characterized by ventricular dilation and impaired systolic function, CC resulting in congestive heart failure and arrhythmia. Patients are at CC risk of premature death. {ECO:0000269|PubMed:17186461, CC ECO:0000269|PubMed:27930341}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Acne inversa, familial, 3 (ACNINV3) [MIM:613737]: A chronic CC relapsing inflammatory disease of the hair follicles characterized by CC recurrent draining sinuses, painful skin abscesses, and disfiguring CC scars. Manifestations typically appear after puberty. CC {ECO:0000269|PubMed:20929727}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Pick disease of the brain (PIDB) [MIM:172700]: A rare form of CC dementia pathologically defined by severe atrophy, neuronal loss and CC gliosis. It is characterized by the occurrence of tau-positive CC inclusions, swollen neurons (Pick cells) and argentophilic neuronal CC inclusions known as Pick bodies that disproportionally affect the CC frontal and temporal cortical regions. Clinical features include CC aphasia, apraxia, confusion, anomia, memory loss and personality CC deterioration. {ECO:0000269|PubMed:15122701}. Note=The gene represented CC in this entry may be involved in disease pathogenesis. CC -!- MISCELLANEOUS: [Isoform 3]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 5]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the peptidase A22A family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Alzheimer Research Forum; Note=Presenilins CC mutations; CC URL="https://www.alzforum.org/mutations/psen-1"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L42110; AAB46416.1; -; mRNA. DR EMBL; L76517; AAB46370.1; -; mRNA. DR EMBL; L76528; AAB46371.1; -; Genomic_DNA. DR EMBL; L76519; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76520; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76521; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76522; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76523; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76524; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76525; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76526; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; L76527; AAB46371.1; JOINED; Genomic_DNA. DR EMBL; U40379; AAB05894.1; -; mRNA. DR EMBL; U40380; AAB05895.1; -; mRNA. DR EMBL; AJ008005; CAA07825.1; -; mRNA. DR EMBL; AF109907; AAC97960.1; -; Genomic_DNA. DR EMBL; AF416717; AAL16811.1; -; mRNA. DR EMBL; AK312531; BAG35430.1; -; mRNA. DR EMBL; AC004858; AAF19253.1; -; Genomic_DNA. DR EMBL; AC004858; AAF19254.1; -; Genomic_DNA. DR EMBL; CH471061; EAW81092.1; -; Genomic_DNA. DR EMBL; BC011729; AAH11729.1; -; mRNA. DR EMBL; D84149; BAA20883.1; -; Genomic_DNA. DR CCDS; CCDS9812.1; -. [P49768-1] DR CCDS; CCDS9813.1; -. [P49768-2] DR PIR; S58396; S58396. DR PIR; S63683; S63683. DR PIR; S63684; S63684. DR RefSeq; NP_000012.1; NM_000021.4. [P49768-1] DR RefSeq; NP_015557.2; NM_007318.3. [P49768-2] DR RefSeq; XP_005267921.1; XM_005267864.4. [P49768-1] DR RefSeq; XP_005267923.1; XM_005267866.3. [P49768-2] DR RefSeq; XP_011535274.1; XM_011536972.3. [P49768-1] DR RefSeq; XP_011535275.1; XM_011536973.3. [P49768-2] DR RefSeq; XP_011535276.1; XM_011536974.3. [P49768-2] DR RefSeq; XP_047287556.1; XM_047431600.1. [P49768-1] DR RefSeq; XP_047287557.1; XM_047431601.1. [P49768-1] DR RefSeq; XP_047287558.1; XM_047431602.1. [P49768-2] DR RefSeq; XP_054232388.1; XM_054376413.1. [P49768-1] DR RefSeq; XP_054232389.1; XM_054376414.1. [P49768-1] DR RefSeq; XP_054232390.1; XM_054376415.1. [P49768-1] DR RefSeq; XP_054232391.1; XM_054376416.1. [P49768-1] DR RefSeq; XP_054232392.1; XM_054376417.1. [P49768-2] DR RefSeq; XP_054232393.1; XM_054376418.1. [P49768-2] DR RefSeq; XP_054232394.1; XM_054376419.1. [P49768-2] DR RefSeq; XP_054232395.1; XM_054376420.1. [P49768-2] DR PDB; 2KR6; NMR; -; A=292-467. DR PDB; 4UIS; EM; 4.40 A; B=81-463. DR PDB; 5A63; EM; 3.40 A; B=1-467. DR PDB; 5FN2; EM; 4.20 A; B=1-467. DR PDB; 5FN3; EM; 4.10 A; B=1-467. DR PDB; 5FN4; EM; 4.00 A; B=1-467. DR PDB; 5FN5; EM; 4.30 A; B=1-467. DR PDB; 6IDF; EM; 2.70 A; B=1-467. DR PDB; 6IYC; EM; 2.60 A; B=1-467. DR PDB; 6LQG; EM; 3.10 A; B=1-467. DR PDB; 6LR4; EM; 3.00 A; B=1-467. DR PDB; 7C9I; EM; 3.10 A; B=1-467. DR PDB; 7D8X; EM; 2.60 A; B=1-467. DR PDB; 7Y5T; EM; 2.90 A; B=1-467. DR PDB; 8IM7; EM; 3.40 A; B=1-467. DR PDB; 8K8E; EM; 2.60 A; B=1-467. DR PDB; 8KCO; EM; 2.80 A; B=1-467. DR PDB; 8KCP; EM; 3.00 A; B=1-467. DR PDB; 8KCS; EM; 2.40 A; B=1-467. DR PDB; 8KCT; EM; 2.60 A; B=1-467. DR PDB; 8KCU; EM; 2.70 A; B=1-467. DR PDB; 8OQY; EM; 3.30 A; B=1-467. DR PDB; 8OQZ; EM; 3.40 A; B=1-467. DR PDB; 8X52; EM; 2.90 A; B=1-467. DR PDB; 8X53; EM; 3.00 A; B=1-467. DR PDB; 8X54; EM; 2.90 A; B=1-467. DR PDBsum; 2KR6; -. DR PDBsum; 4UIS; -. DR PDBsum; 5A63; -. DR PDBsum; 5FN2; -. DR PDBsum; 5FN3; -. DR PDBsum; 5FN4; -. DR PDBsum; 5FN5; -. DR PDBsum; 6IDF; -. DR PDBsum; 6IYC; -. DR PDBsum; 6LQG; -. DR PDBsum; 6LR4; -. DR PDBsum; 7C9I; -. DR PDBsum; 7D8X; -. DR PDBsum; 7Y5T; -. DR PDBsum; 8IM7; -. DR PDBsum; 8K8E; -. DR PDBsum; 8KCO; -. DR PDBsum; 8KCP; -. DR PDBsum; 8KCS; -. DR PDBsum; 8KCT; -. DR PDBsum; 8KCU; -. DR PDBsum; 8OQY; -. DR PDBsum; 8OQZ; -. DR PDBsum; 8X52; -. DR PDBsum; 8X53; -. DR PDBsum; 8X54; -. DR AlphaFoldDB; P49768; -. DR EMDB; EMD-0944; -. DR EMDB; EMD-0957; -. DR EMDB; EMD-17112; -. DR EMDB; EMD-17113; -. DR EMDB; EMD-2477; -. DR EMDB; EMD-2478; -. DR EMDB; EMD-30312; -. DR EMDB; EMD-30614; -. DR EMDB; EMD-33624; -. DR EMDB; EMD-35572; -. DR EMDB; EMD-36948; -. DR EMDB; EMD-37106; -. DR EMDB; EMD-37107; -. DR EMDB; EMD-37108; -. DR EMDB; EMD-37109; -. DR EMDB; EMD-37110; -. DR EMDB; EMD-38059; -. DR EMDB; EMD-38060; -. DR EMDB; EMD-38061; -. DR EMDB; EMD-9648; -. DR EMDB; EMD-9751; -. DR SMR; P49768; -. DR BioGRID; 111642; 203. DR ComplexPortal; CPX-2176; Gamma-secretase complex, APH1A-PSEN1 variant. DR ComplexPortal; CPX-4233; Gamma-secretase complex, APH1B-PSEN1 variant. DR CORUM; P49768; -. DR DIP; DIP-1134N; -. DR ELM; P49768; -. DR FunCoup; P49768; 2287. DR IntAct; P49768; 299. DR MINT; P49768; -. DR STRING; 9606.ENSP00000326366; -. DR BindingDB; P49768; -. DR ChEMBL; CHEMBL2473; -. DR DrugBank; DB11893; Avagacestat. DR DrugBank; DB12263; Begacestat. DR DrugBank; DB05171; E-2012. DR DrugBank; DB16159; Esflurbiprofen. DR DrugBank; DB12819; GSI-136. DR DrugBank; DB16825; Itanapraced. DR DrugBank; DB12852; MK-0752. DR DrugBank; DB12005; Nirogacestat. DR DrugBank; DB11870; RG-4733. DR DrugBank; DB12463; Semagacestat. DR DrugBank; DB05289; Tarenflurbil. DR GuidetoPHARMACOLOGY; 2402; -. DR MEROPS; A22.001; -. DR TCDB; 1.A.54.1.1; the presenilin er ca(2+) leak channel (presenilin) family. DR iPTMnet; P49768; -. DR PhosphoSitePlus; P49768; -. DR SwissPalm; P49768; -. DR BioMuta; PSEN1; -. DR DMDM; 1709856; -. DR jPOST; P49768; -. DR MassIVE; P49768; -. DR PaxDb; 9606-ENSP00000326366; -. DR PeptideAtlas; P49768; -. DR ProteomicsDB; 56106; -. [P49768-1] DR ProteomicsDB; 56107; -. [P49768-2] DR ProteomicsDB; 56108; -. [P49768-3] DR ProteomicsDB; 56109; -. [P49768-4] DR ProteomicsDB; 56110; -. [P49768-5] DR ProteomicsDB; 56111; -. [P49768-6] DR ProteomicsDB; 56112; -. [P49768-7] DR Pumba; P49768; -. DR Antibodypedia; 3480; 972 antibodies from 47 providers. DR DNASU; 5663; -. DR Ensembl; ENST00000324501.10; ENSP00000326366.5; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000357710.8; ENSP00000350342.4; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000394157.7; ENSP00000377712.3; ENSG00000080815.21. [P49768-4] DR Ensembl; ENST00000394164.5; ENSP00000377719.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000553599.6; ENSP00000452477.2; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000553855.5; ENSP00000452242.1; ENSG00000080815.21. [P49768-5] DR Ensembl; ENST00000554131.6; ENSP00000451915.2; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000555386.6; ENSP00000450845.1; ENSG00000080815.21. [P49768-3] DR Ensembl; ENST00000556951.6; ENSP00000450551.2; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000557511.5; ENSP00000451429.1; ENSG00000080815.21. [P49768-6] DR Ensembl; ENST00000700265.1; ENSP00000514901.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700267.1; ENSP00000514903.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700268.1; ENSP00000514904.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700269.1; ENSP00000514905.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700273.1; ENSP00000514908.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700306.1; ENSP00000514933.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700313.1; ENSP00000514940.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700317.1; ENSP00000514944.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700321.1; ENSP00000514948.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700322.1; ENSP00000514949.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700323.1; ENSP00000514950.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700324.1; ENSP00000514951.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700375.1; ENSP00000514966.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700378.1; ENSP00000514968.1; ENSG00000080815.21. [P49768-1] DR Ensembl; ENST00000700389.1; ENSP00000514970.1; ENSG00000080815.21. [P49768-2] DR Ensembl; ENST00000700436.1; ENSP00000514987.1; ENSG00000080815.21. [P49768-5] DR Ensembl; ENST00000700469.1; ENSP00000515002.1; ENSG00000080815.21. [P49768-2] DR GeneID; 5663; -. DR KEGG; hsa:5663; -. DR MANE-Select; ENST00000324501.10; ENSP00000326366.5; NM_000021.4; NP_000012.1. DR UCSC; uc001xnq.5; human. [P49768-1] DR AGR; HGNC:9508; -. DR ClinPGx; PA33855; -. DR CTD; 5663; -. DR DisGeNET; 5663; -. DR GeneCards; PSEN1; -. DR GeneReviews; PSEN1; -. DR HGNC; HGNC:9508; PSEN1. DR HPA; ENSG00000080815; Low tissue specificity. DR MalaCards; PSEN1; -. DR MIM; 104311; gene. DR MIM; 172700; phenotype. DR MIM; 600274; phenotype. DR MIM; 607822; phenotype. DR MIM; 613694; phenotype. DR MIM; 613737; phenotype. DR OpenTargets; ENSG00000080815; -. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease. DR Orphanet; 154; Familial isolated dilated cardiomyopathy. DR Orphanet; 100070; Progressive non-fluent aphasia. DR Orphanet; 100069; Semantic dementia. DR VEuPathDB; HostDB:ENSG00000080815; -. DR eggNOG; KOG2736; Eukaryota. DR GeneTree; ENSGT00940000158751; -. DR HOGENOM; CLU_022975_3_0_1; -. DR InParanoid; P49768; -. DR OMA; NATCNQQ; -. DR OrthoDB; 20287at2759; -. DR PAN-GO; P49768; 26 GO annotations based on evolutionary models. DR PhylomeDB; P49768; -. DR PathwayCommons; P49768; -. DR Reactome; R-HSA-1251985; Nuclear signaling by ERBB4. DR Reactome; R-HSA-1474228; Degradation of the extracellular matrix. DR Reactome; R-HSA-193692; Regulated proteolysis of p75NTR. DR Reactome; R-HSA-205043; NRIF signals cell death from the nucleus. DR Reactome; R-HSA-2122948; Activated NOTCH1 Transmits Signal to the Nucleus. DR Reactome; R-HSA-2644606; Constitutive Signaling by NOTCH1 PEST Domain Mutants. DR Reactome; R-HSA-2894862; Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants. DR Reactome; R-HSA-2979096; NOTCH2 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-3928665; EPH-ephrin mediated repulsion of cells. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR Reactome; R-HSA-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-9013700; NOTCH4 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-9017802; Noncanonical activation of NOTCH3. DR Reactome; R-HSA-9839383; TGFBR3 PTM regulation. DR SignaLink; P49768; -. DR SIGNOR; P49768; -. DR Agora; ENSG00000080815; -. DR BioGRID-ORCS; 5663; 16 hits in 1162 CRISPR screens. DR CD-CODE; 8C2F96ED; Centrosome. DR ChiTaRS; PSEN1; human. DR EvolutionaryTrace; P49768; -. DR GeneWiki; PSEN1; -. DR GenomeRNAi; 5663; -. DR Pharos; P49768; Tchem. DR PRO; PR:P49768; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; P49768; protein. DR Bgee; ENSG00000080815; Expressed in middle frontal gyrus and 202 other cell types or tissues. DR ExpressionAtlas; P49768; baseline and differential. DR GO; GO:0016235; C:aggresome; IDA:UniProtKB. DR GO; GO:0035577; C:azurophil granule membrane; TAS:Reactome. DR GO; GO:0005938; C:cell cortex; IEA:Ensembl. DR GO; GO:0030054; C:cell junction; IDA:HPA. DR GO; GO:0009986; C:cell surface; IEA:Ensembl. DR GO; GO:0005813; C:centrosome; IDA:UniProtKB. DR GO; GO:0035253; C:ciliary rootlet; IEA:Ensembl. DR GO; GO:0030425; C:dendrite; IDA:ARUK-UCL. DR GO; GO:0043198; C:dendritic shaft; IEA:Ensembl. DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HGNC-UCL. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0070765; C:gamma-secretase complex; IDA:UniProtKB. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0030426; C:growth cone; IDA:UniProtKB. DR GO; GO:0000776; C:kinetochore; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0045121; C:membrane raft; IDA:UniProtKB. DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:Ensembl. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0031594; C:neuromuscular junction; IEA:Ensembl. DR GO; GO:0043005; C:neuron projection; IDA:UniProtKB. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0031965; C:nuclear membrane; IDA:UniProtKB. DR GO; GO:0005640; C:nuclear outer membrane; IDA:MGI. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IMP:CAFA. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0098794; C:postsynapse; IEA:GOC. DR GO; GO:0042734; C:presynaptic membrane; IEA:Ensembl. DR GO; GO:0032991; C:protein-containing complex; IMP:CAFA. DR GO; GO:0005791; C:rough endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0042383; C:sarcolemma; IEA:Ensembl. DR GO; GO:0005790; C:smooth endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0008021; C:synaptic vesicle; IEA:Ensembl. DR GO; GO:0042500; F:aspartic endopeptidase activity, intramembrane cleaving; IDA:UniProtKB. DR GO; GO:0004190; F:aspartic-type endopeptidase activity; NAS:ARUK-UCL. DR GO; GO:0051117; F:ATPase binding; IPI:ARUK-UCL. DR GO; GO:0008013; F:beta-catenin binding; IPI:UniProtKB. DR GO; GO:0045296; F:cadherin binding; IEA:Ensembl. DR GO; GO:0005262; F:calcium channel activity; IMP:UniProtKB. DR GO; GO:0004175; F:endopeptidase activity; IDA:MGI. DR GO; GO:0070851; F:growth factor receptor binding; IPI:ARUK-UCL. DR GO; GO:0060090; F:molecular adaptor activity; IDA:UniProtKB. DR GO; GO:0030165; F:PDZ domain binding; IPI:UniProtKB. DR GO; GO:0042987; P:amyloid precursor protein catabolic process; IDA:ARUK-UCL. DR GO; GO:0042982; P:amyloid precursor protein metabolic process; IDA:UniProtKB. DR GO; GO:0034205; P:amyloid-beta formation; IDA:ARUK-UCL. DR GO; GO:0097190; P:apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0048143; P:astrocyte activation; IGI:ARUK-UCL. DR GO; GO:0002265; P:astrocyte activation involved in immune response; IGI:ARUK-UCL. DR GO; GO:0000045; P:autophagosome assembly; IEA:Ensembl. DR GO; GO:0001568; P:blood vessel development; IEA:Ensembl. DR GO; GO:0048854; P:brain morphogenesis; IEA:Ensembl. DR GO; GO:0021870; P:Cajal-Retzius cell differentiation; IEA:Ensembl. DR GO; GO:0055074; P:calcium ion homeostasis; IBA:GO_Central. DR GO; GO:0001708; P:cell fate specification; IEA:Ensembl. DR GO; GO:0098609; P:cell-cell adhesion; IMP:MGI. DR GO; GO:1904646; P:cellular response to amyloid-beta; IGI:ARUK-UCL. DR GO; GO:0021549; P:cerebellum development; IEA:Ensembl. DR GO; GO:0021795; P:cerebral cortex cell migration; IEA:Ensembl. DR GO; GO:0015871; P:choline transport; IEA:Ensembl. DR GO; GO:0006974; P:DNA damage response; IDA:ARUK-UCL. DR GO; GO:0021904; P:dorsal/ventral neural tube patterning; IEA:Ensembl. DR GO; GO:0030326; P:embryonic limb morphogenesis; IEA:Ensembl. DR GO; GO:0032469; P:endoplasmic reticulum calcium ion homeostasis; IDA:MGI. DR GO; GO:0050673; P:epithelial cell proliferation; IEA:Ensembl. DR GO; GO:0001947; P:heart looping; IEA:Ensembl. DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IEA:Ensembl. DR GO; GO:0035556; P:intracellular signal transduction; IMP:UniProtKB. DR GO; GO:0098712; P:L-glutamate import across plasma membrane; IEA:Ensembl. DR GO; GO:0007611; P:learning or memory; IGI:ARUK-UCL. DR GO; GO:0040011; P:locomotion; IEA:Ensembl. DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:HGNC-UCL. DR GO; GO:0007613; P:memory; IGI:ARUK-UCL. DR GO; GO:0006839; P:mitochondrial transport; IEA:Ensembl. DR GO; GO:0043011; P:myeloid dendritic cell differentiation; IEA:Ensembl. DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:2001234; P:negative regulation of apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0050771; P:negative regulation of axonogenesis; IEA:Ensembl. DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; IEA:Ensembl. DR GO; GO:0010629; P:negative regulation of gene expression; IGI:ARUK-UCL. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:2000059; P:negative regulation of ubiquitin-dependent protein catabolic process; IEA:Ensembl. DR GO; GO:0003407; P:neural retina development; IEA:Ensembl. DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl. DR GO; GO:0070050; P:neuron cellular homeostasis; IEA:Ensembl. DR GO; GO:0048666; P:neuron development; IEA:Ensembl. DR GO; GO:0001764; P:neuron migration; IEA:Ensembl. DR GO; GO:1990535; P:neuron projection maintenance; IGI:ARUK-UCL. DR GO; GO:0007220; P:Notch receptor processing; IDA:ARUK-UCL. DR GO; GO:0007219; P:Notch signaling pathway; IBA:GO_Central. DR GO; GO:1905908; P:positive regulation of amyloid fibril formation; IGI:ARUK-UCL. DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0050820; P:positive regulation of coagulation; IEA:Ensembl. DR GO; GO:0060999; P:positive regulation of dendritic spine development; IMP:CACAO. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IMP:CACAO. DR GO; GO:0010628; P:positive regulation of gene expression; IGI:ARUK-UCL. DR GO; GO:0045821; P:positive regulation of glycolytic process; IGI:ARUK-UCL. DR GO; GO:0002038; P:positive regulation of L-glutamate import across plasma membrane; IEA:Ensembl. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IEA:Ensembl. DR GO; GO:0001921; P:positive regulation of receptor recycling; IEA:Ensembl. DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IGI:ARUK-UCL. DR GO; GO:0009791; P:post-embryonic development; IEA:Ensembl. DR GO; GO:0140249; P:protein catabolic process at postsynapse; IEA:Ensembl. DR GO; GO:0016485; P:protein processing; IDA:HGNC-UCL. DR GO; GO:0015031; P:protein transport; IEA:Ensembl. DR GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; ISS:UniProtKB. DR GO; GO:0010468; P:regulation of gene expression; IGI:ARUK-UCL. DR GO; GO:0010975; P:regulation of neuron projection development; IMP:UniProtKB. DR GO; GO:0099175; P:regulation of postsynapse organization; IEA:Ensembl. DR GO; GO:0060075; P:regulation of resting membrane potential; IEA:Ensembl. DR GO; GO:0048167; P:regulation of synaptic plasticity; IEA:Ensembl. DR GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; IEA:Ensembl. DR GO; GO:0098693; P:regulation of synaptic vesicle cycle; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; IEA:Ensembl. DR GO; GO:0051208; P:sequestering of calcium ion; IEA:Ensembl. DR GO; GO:0048705; P:skeletal system morphogenesis; IEA:Ensembl. DR GO; GO:0043589; P:skin morphogenesis; IEA:Ensembl. DR GO; GO:0051563; P:smooth endoplasmic reticulum calcium ion homeostasis; IEA:Ensembl. DR GO; GO:0001756; P:somitogenesis; IEA:Ensembl. DR GO; GO:0050808; P:synapse organization; IGI:ARUK-UCL. DR GO; GO:0016080; P:synaptic vesicle targeting; IEA:Ensembl. DR GO; GO:0002286; P:T cell activation involved in immune response; IEA:Ensembl. DR GO; GO:0050852; P:T cell receptor signaling pathway; IEA:Ensembl. DR GO; GO:0048538; P:thymus development; IEA:Ensembl. DR DisProt; DP01292; -. DR FunFam; 1.10.472.100:FF:000001; Presenilin; 1. DR Gene3D; 1.10.472.100; Presenilin; 1. DR InterPro; IPR002031; Pept_A22A_PS1. DR InterPro; IPR001108; Peptidase_A22A. DR InterPro; IPR006639; Preselin/SPP. DR InterPro; IPR042524; Presenilin_C. DR PANTHER; PTHR10202; PRESENILIN; 1. DR PANTHER; PTHR10202:SF18; PRESENILIN-1; 1. DR Pfam; PF01080; Presenilin; 1. DR PRINTS; PR01072; PRESENILIN. DR PRINTS; PR01073; PRESENILIN1. DR SMART; SM00730; PSN; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Alzheimer disease; Amyloidosis; KW Apoptosis; Cardiomyopathy; Cell adhesion; Cell membrane; Cell projection; KW Direct protein sequencing; Disease variant; Endoplasmic reticulum; KW Endosome; Golgi apparatus; Hydrolase; Membrane; Neurodegeneration; KW Notch signaling pathway; Phosphoprotein; Protease; KW Proteomics identification; Reference proteome; Synapse; Transmembrane; KW Transmembrane helix. FT CHAIN 1..298 FT /note="Presenilin-1 NTF subunit" FT /evidence="ECO:0000269|PubMed:9173929" FT /id="PRO_0000025591" FT CHAIN 299..467 FT /note="Presenilin-1 CTF subunit" FT /evidence="ECO:0000269|PubMed:9173929" FT /id="PRO_0000025592" FT CHAIN 346..467 FT /note="Presenilin-1 CTF12" FT /evidence="ECO:0000269|PubMed:9485372" FT /id="PRO_0000236055" FT TOPO_DOM 1..82 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 83..103 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 104..132 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 133..153 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 154..166 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 167..189 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 190..194 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 195..216 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 217..220 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 221..241 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 242..248 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 249..272 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 273..380 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 381..401 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 402..407 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 408..428 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 429..432 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335" FT TRANSMEM 433..453 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 454..467 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335" FT REGION 13..68 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 288..290 FT /note="Important for cleavage of target proteins" FT /evidence="ECO:0000269|PubMed:30598546" FT REGION 305..333 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 322..450 FT /note="Required for interaction with CTNNB1" FT /evidence="ECO:0000269|PubMed:9738936" FT REGION 372..399 FT /note="Required for interaction with CTNND2" FT /evidence="ECO:0000269|PubMed:10037471" FT REGION 377..381 FT /note="Important for cleavage of target proteins" FT /evidence="ECO:0000269|PubMed:30598546" FT REGION 432..434 FT /note="Important for cleavage of target proteins" FT /evidence="ECO:0000269|PubMed:30598546" FT REGION 464..467 FT /note="Interaction with MTCH1" FT /evidence="ECO:0000269|PubMed:10551805" FT MOTIF 433..435 FT /note="PAL" FT /evidence="ECO:0000305|PubMed:16305624" FT COMPBIAS 13..29 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 30..45 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 257 FT /evidence="ECO:0000305|PubMed:10206644, FT ECO:0000305|PubMed:10899933, ECO:0000305|PubMed:15341515" FT ACT_SITE 385 FT /evidence="ECO:0000305|PubMed:10206644, FT ECO:0000305|PubMed:10899933, ECO:0000305|PubMed:15341515, FT ECO:0000305|PubMed:30598546, ECO:0000305|PubMed:30630874" FT SITE 291..292 FT /note="Cleavage; alternate" FT /evidence="ECO:0000269|PubMed:9173929" FT SITE 292..293 FT /note="Cleavage; alternate" FT /evidence="ECO:0000269|PubMed:9173929" FT SITE 298..299 FT /note="Cleavage" FT /evidence="ECO:0000269|PubMed:9173929" FT SITE 345..346 FT /note="Cleavage; by caspase" FT /evidence="ECO:0000269|PubMed:9485372" FT MOD_RES 43 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17081983, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 51 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P97887" FT MOD_RES 310 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000269|PubMed:14576165" FT MOD_RES 346 FT /note="Phosphoserine; by PKC" FT /evidence="ECO:0000269|PubMed:14576165" FT MOD_RES 367 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT VAR_SEQ 26..29 FT /note="Missing (in isoform 2 and isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:7596406, ECO:0000303|PubMed:8641442" FT /id="VSP_005191" FT VAR_SEQ 162..184 FT /note="IHAWLIISSLLLLFFFSFIYLGE -> SMRHRSLLSTLFFLWLGILVTVT FT (in isoform 4)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_007986" FT VAR_SEQ 185..467 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_007987" FT VAR_SEQ 257..289 FT /note="Missing (in isoform 7)" FT /evidence="ECO:0000305" FT /id="VSP_041440" FT VAR_SEQ 319..467 FT /note="STERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAAVQELSSSILA FT GEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCLTLLLLAIFK FT KALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI -> RACLPPAAINLLSIAPM FT APRLFMPKGACRPTAQKGSHKTLLQRMMMAGSVRNGKPRGTVI (in isoform 3 FT and isoform 5)" FT /evidence="ECO:0000303|PubMed:8641442, ECO:0000303|Ref.5" FT /id="VSP_005192" FT VAR_SEQ 319..376 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000305" FT /id="VSP_012288" FT VARIANT 35 FT /note="R -> Q (in AD3; uncertain significance; decreased FT protease activity with APP; dbSNP:rs63750592)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075260" FT VARIANT 79 FT /note="A -> V (in AD3; also found in late-onset Alzheimer FT disease; impaired protease activity with APP; results in FT altered amyloid-beta production and increased amyloid-beta FT 42/amyloid-beta 40 ratio; no effect on interaction with FT GFAP; dbSNP:rs63749824)" FT /evidence="ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:12058025, FT ECO:0000269|PubMed:16752394, ECO:0000269|PubMed:17366635, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9384602" FT /id="VAR_006413" FT VARIANT 82 FT /note="V -> L (in AD3; decreased protease activity with FT APP; no effect on interaction with GFAP; dbSNP:rs63749967)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:12058025, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712" FT /id="VAR_006414" FT VARIANT 83 FT /note="I -> T (in AD3)" FT /evidence="ECO:0000269|PubMed:26145164" FT /id="VAR_075261" FT VARIANT 85 FT /note="L -> P (in AD3; the patient also manifest spastic FT paraparesis and apraxia; loss of protease activity with APP FT in vitro; altered amyloid-beta production in cells FT transfected with the mutant and increased amyloid-beta 42/ FT amyloid-beta 40 ratio; dbSNP:rs63750599)" FT /evidence="ECO:0000269|PubMed:15534188, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081228" FT VARIANT 89 FT /note="V -> L (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750815)" FT /evidence="ECO:0000269|PubMed:11796781" FT /id="VAR_081229" FT VARIANT 92 FT /note="C -> S (in AD3; loss of protease activity with APP; FT dbSNP:rs63751141)" FT /evidence="ECO:0000269|PubMed:11027672, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016214" FT VARIANT 94 FT /note="V -> M (in AD3; uncertain significance; reduced FT protease activity with APP; no relevant change in amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs63750831)" FT /evidence="ECO:0000269|PubMed:11568920" FT /id="VAR_081230" FT VARIANT 96 FT /note="V -> F (in AD3; loss of protease activity with APP; FT dbSNP:rs63750601)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8733303" FT /id="VAR_006415" FT VARIANT 97 FT /note="V -> L (in AD3; uncertain significance; slightly FT reduced protease activity with APP; dbSNP:rs63750852)" FT /evidence="ECO:0000269|PubMed:15851849, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081231" FT VARIANT 105 FT /note="F -> L (in AD3; dbSNP:rs63750321)" FT /evidence="ECO:0000269|PubMed:10631141" FT /id="VAR_009208" FT VARIANT 113 FT /note="L -> P (in FTD1; dbSNP:rs63751399)" FT /evidence="ECO:0000269|PubMed:11094121" FT /id="VAR_016215" FT VARIANT 115 FT /note="Y -> C (in AD3; dbSNP:rs63750450)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:12552037, ECO:0000269|PubMed:9384602" FT /id="VAR_006416" FT VARIANT 115 FT /note="Y -> H (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:8634712" FT /id="VAR_006417" FT VARIANT 116 FT /note="T -> I (in AD3; dbSNP:rs63750730)" FT /evidence="ECO:0000269|PubMed:30200536" FT /id="VAR_081232" FT VARIANT 116 FT /note="T -> N (in AD3; unusual amyloid cotton wool plaques FT detected in one patient's brain; severe decrease of FT protease activity with APP; results in increased amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs63750730)" FT /evidence="ECO:0000269|PubMed:10439444, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:29404783" FT /id="VAR_010120" FT VARIANT 117 FT /note="P -> L (in AD3; impaired ability to cleave Ephb2/ FT CTF1; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; impaired FT regulation of neurite outgrowth; dbSNP:rs63749805)" FT /evidence="ECO:0000269|PubMed:15004326, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:9507958" FT /id="VAR_009209" FT VARIANT 117 FT /note="P -> S (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; impaired regulation of neurite outgrowth; FT dbSNP:rs63750550)" FT /evidence="ECO:0000269|PubMed:15004326" FT /id="VAR_081233" FT VARIANT 120 FT /note="E -> D (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751272)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9521423" FT /id="VAR_006418" FT VARIANT 120 FT /note="E -> K (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750800)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006419" FT VARIANT 134 FT /note="L -> R (in AD3; uncertain significance; loss of FT protease activity with APP; dbSNP:rs1595002439)" FT /evidence="ECO:0000269|PubMed:22503161, FT ECO:0000269|PubMed:27930341" FT /id="VAR_070023" FT VARIANT 135 FT /note="N -> D (in AD3; impaired protease activity with APP FT and increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750353)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:9225696" FT /id="VAR_010121" FT VARIANT 139 FT /note="M -> I (in AD3; dbSNP:rs63750522)" FT /evidence="ECO:0000269|PubMed:8875251" FT /id="VAR_006420" FT VARIANT 139 FT /note="M -> K (in AD3; dbSNP:rs63751106)" FT /evidence="ECO:0000269|PubMed:9719376" FT /id="VAR_010122" FT VARIANT 139 FT /note="M -> T (in AD3; dbSNP:rs63751106)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:8634712" FT /id="VAR_006421" FT VARIANT 139 FT /note="M -> V (in AD3; increased amyloid-beta 42/amyloid- FT beta 40 ratio; dbSNP:rs63751037)" FT /evidence="ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7550356" FT /id="VAR_006422" FT VARIANT 142 FT /note="V -> F (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:29175279" FT /id="VAR_081234" FT VARIANT 143 FT /note="I -> F (in AD3; dbSNP:rs63750322)" FT /evidence="ECO:0000269|PubMed:10090481" FT /id="VAR_006423" FT VARIANT 143 FT /note="I -> T (in AD3; impaired protease activity with APP; FT results in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750004)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:11568920, ECO:0000269|PubMed:15122701, FT ECO:0000269|PubMed:16752394, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634711" FT /id="VAR_006424" FT VARIANT 146 FT /note="M -> I (in AD3; dbSNP:rs63750391)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:12552037" FT /id="VAR_006425" FT VARIANT 146 FT /note="M -> L (in AD3; disease phenotype shows high FT clinical variability; founder mutation originating from FT Southern Italy and distributed worldwide; alters the FT conformation of the active site; slightly increased FT protease activity with APP; decreased activity for Notch1 FT cleavage; no loss of its ability to cleave Ephb2/CTF1; FT dbSNP:rs63750306)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:17428795, FT ECO:0000269|PubMed:20164095, ECO:0000269|PubMed:22461631, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7596406" FT /id="VAR_006426" FT VARIANT 146 FT /note="M -> V (in AD3; loss of function as calcium-leak FT channel; results in calcium overload in the endoplasmic FT reticulum; dbSNP:rs63750306)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:16959576, ECO:0000269|PubMed:7550356" FT /id="VAR_006427" FT VARIANT 147 FT /note="T -> I (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750907)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010123" FT VARIANT 153 FT /note="L -> V (in AD3; abolishes protease activity with APP FT resulting in decreased amyloid-beta 42 and amyloid-beta 40 FT production; dbSNP:rs63751441)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:24495933, ECO:0000269|PubMed:27930341" FT /id="VAR_081235" FT VARIANT 154 FT /note="Y -> C (in AD3; uncertain significance; FT dbSNP:rs63751292)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081236" FT VARIANT 154 FT /note="Y -> N (in AD3; disease phenotype includes spastic FT paraparesis; abolishes protease activity with APP resulting FT in decreased amyloid-beta 42 and amyloid-beta 40 FT production; dbSNP:rs63750588)" FT /evidence="ECO:0000269|PubMed:15364419, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081237" FT VARIANT 156 FT /note="Y -> FTY (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075262" FT VARIANT 159 FT /note="Y -> F (in AD3; uncertain significance; FT dbSNP:rs778630379)" FT /evidence="ECO:0000269|PubMed:23123781" FT /id="VAR_081238" FT VARIANT 163 FT /note="H -> R (in AD3; abolishes protease activity with FT APP; decreased activity for Notch cleavage; FT dbSNP:rs63750590)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:22461631, FT ECO:0000269|PubMed:22503161, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:8634712, FT ECO:0000269|PubMed:8733303, ECO:0000269|PubMed:9521423" FT /id="VAR_006428" FT VARIANT 163 FT /note="H -> Y (in AD3; slightly increased protease activity FT with APP and slightly increased amyloid-beta 42 production; FT dbSNP:rs63749885)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7550356" FT /id="VAR_006429" FT VARIANT 165 FT /note="W -> C (in AD3; dbSNP:rs63751484)" FT /evidence="ECO:0000269|PubMed:10441572" FT /id="VAR_010124" FT VARIANT 166 FT /note="L -> P (in AD3; onset in adolescence; severe FT decrease of protease activity with APP; results in altered FT amyloid-beta production and increased amyloid-beta 42/ FT amyloid-beta 40 ratio; results in reduced Notch FT proteolysis; dbSNP:rs63750265)" FT /evidence="ECO:0000269|PubMed:12048239, FT ECO:0000269|PubMed:22529981, ECO:0000269|PubMed:23843529, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016216" FT VARIANT 168 FT /note="Missing (in AD3; uncertain significance; abolishes FT protease activity with APP resulting in decreased amyloid- FT beta 42 and amyloid-beta 40 production)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081239" FT VARIANT 169 FT /note="S -> L (in AD3; dbSNP:rs63751210)" FT /evidence="ECO:0000269|PubMed:9831473" FT /id="VAR_006430" FT VARIANT 169 FT /note="S -> P (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750418)" FT /evidence="ECO:0000269|PubMed:10025789, FT ECO:0000269|PubMed:27930341" FT /id="VAR_006431" FT VARIANT 170 FT /note="S -> F (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750577)" FT /evidence="ECO:0000269|PubMed:16344340, FT ECO:0000269|PubMed:17502474, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:29466804" FT /id="VAR_081240" FT VARIANT 171 FT /note="L -> P (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750963)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9833068" FT /id="VAR_006432" FT VARIANT 173 FT /note="L -> W (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750299)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010125" FT VARIANT 174 FT /note="L -> M (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751144)" FT /evidence="ECO:0000269|PubMed:12484344, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016217" FT VARIANT 177 FT /note="F -> L (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63749911)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075263" FT VARIANT 177 FT /note="F -> S (in AD3; uncertain significance; FT dbSNP:rs63749806)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075264" FT VARIANT 178 FT /note="S -> P (in AD3; uncertain significance; abolishes FT protease activity with APP; dbSNP:rs63750155)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075265" FT VARIANT 183 FT /note="G -> V (in PIDB and AD3; uncertain significance; FT neuropathologic examination of brain sections from a FT patient shows the presence of Pick bodies and absence of FT beta-amyloid plaques; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio in vitro; dbSNP:rs63751068)" FT /evidence="ECO:0000269|PubMed:15122701, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081241" FT VARIANT 184 FT /note="E -> D (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750311)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081242" FT VARIANT 205 FT /note="F -> L (in dbSNP:rs1042864)" FT /id="VAR_011876" FT VARIANT 206 FT /note="G -> A (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750082)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:11710891, ECO:0000269|PubMed:27073747, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016218" FT VARIANT 206 FT /note="G -> D (in AD3; affects APP processing resulting in FT increased amyloid-beta 42/amyloid-beta 40 ratio; does not FT affect NOTCH processing; does not affect endoproteolysis; FT reduced interaction with PEN2; results in decreased protein FT levels in the endoplasmic reticulum but increased levels in FT early endosome; reduced ability to maintain ER calcium FT homeostasis; dbSNP:rs63750082)" FT /evidence="ECO:0000269|PubMed:21335660, FT ECO:0000269|PubMed:25394380, ECO:0000269|PubMed:29175279" FT /id="VAR_081243" FT VARIANT 206 FT /note="G -> S (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750569)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075266" FT VARIANT 209 FT /note="G -> E (in AD3; uncertain significance; FT dbSNP:rs63750053)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075267" FT VARIANT 209 FT /note="G -> R (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63749880)" FT /evidence="ECO:0000269|PubMed:10447269, FT ECO:0000269|PubMed:27930341" FT /id="VAR_009210" FT VARIANT 209 FT /note="G -> V (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750053)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:9521423" FT /id="VAR_006433" FT VARIANT 213 FT /note="I -> L (in AD3; increases protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750861)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341" FT /id="VAR_075268" FT VARIANT 213 FT /note="I -> T (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63751309)" FT /evidence="ECO:0000269|PubMed:18430735, FT ECO:0000269|PubMed:8733303" FT /id="VAR_006434" FT VARIANT 214 FT /note="H -> Y (found in a patient with dementia; uncertain FT significance; dbSNP:rs63751003)" FT /evidence="ECO:0000269|PubMed:22503161" FT /id="VAR_070024" FT VARIANT 217 FT /note="G -> R (in AD3; with unusual amyloid cotton wool FT plaques; decreased protease activity with APP resulting in FT altered amyloid-beta production and increased amyloid-beta FT 42/amyloid-beta 40 ratio; dbSNP:rs267606983)" FT /evidence="ECO:0000269|PubMed:19667325, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081244" FT VARIANT 219 FT /note="L -> P (in AD3; dbSNP:rs63750761)" FT /evidence="ECO:0000269|PubMed:10208579" FT /id="VAR_010126" FT VARIANT 222 FT /note="Q -> R (in AD3; uncertain significance; slightly FT increased protease activity with APP and slightly increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750009)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075269" FT VARIANT 229 FT /note="I -> F (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63749970)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081245" FT VARIANT 231 FT /note="A -> T (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63749836)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712" FT /id="VAR_006435" FT VARIANT 231 FT /note="A -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750799)" FT /evidence="ECO:0000269|PubMed:16752394, FT ECO:0000269|PubMed:9384602" FT /id="VAR_006436" FT VARIANT 233 FT /note="M -> L (in AD3; slightly decreased protease activity FT with APP resulting in altered amyloid-beta production and FT mildly increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751287)" FT /evidence="ECO:0000269|PubMed:10533070, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341" FT /id="VAR_009211" FT VARIANT 233 FT /note="M -> T (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63751024)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9172170" FT /id="VAR_006437" FT VARIANT 235 FT /note="L -> P (in AD3; abolishes protease activity with FT APP; dbSNP:rs63749835)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341" FT /id="VAR_006438" FT VARIANT 235 FT /note="L -> R (in AD3; abolishes protease activity with FT APP)" FT /evidence="ECO:0000269|PubMed:21501661, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081246" FT VARIANT 235 FT /note="L -> V (in AD3; reduced APP cleavage resulting in FT decreased amyloid-beta 42 and amyloid-beta 40 production; FT no relevant change in amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751130)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081247" FT VARIANT 237 FT /note="F -> I (in AD3; uncertain significance; disease FT phenotype includes spastic paraparesis; severe decrease of FT protease activity with APP; results in decreased amyloid- FT beta 42 and amyloid-beta 40 production; dbSNP:rs63750858)" FT /evidence="ECO:0000269|PubMed:11561050, FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341" FT /id="VAR_081248" FT VARIANT 237 FT /note="F -> L (in AD3; uncertain significance; FT dbSNP:rs63750858)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081249" FT VARIANT 246 FT /note="A -> E (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT no loss of its ability to cleave Ephb2/CTF1; FT dbSNP:rs63750526)" FT /evidence="ECO:0000269|PubMed:17428795, FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7596406" FT /id="VAR_006439" FT VARIANT 250 FT /note="L -> S (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751163)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006440" FT VARIANT 260 FT /note="A -> V (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT impaired ability to cleave Ephb2/CTF1; dbSNP:rs63751420)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:9521423" FT /id="VAR_006441" FT VARIANT 261 FT /note="V -> F (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750964)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341" FT /id="VAR_075270" FT VARIANT 262 FT /note="L -> F (in AD3; decreased protease activity with APP FT resulting in altered amyloid-beta production and increased FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750248)" FT /evidence="ECO:0000269|PubMed:16752394, FT ECO:0000269|PubMed:27930341" FT /id="VAR_006442" FT VARIANT 262 FT /note="L -> V (in AD3)" FT /evidence="ECO:0000269|PubMed:22503161" FT /id="VAR_070025" FT VARIANT 263 FT /note="C -> F (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751102)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:16752394" FT /id="VAR_081250" FT VARIANT 263 FT /note="C -> R (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750543)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006443" FT VARIANT 264 FT /note="P -> L (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT impaired ability to cleave Ephb2/CTF1; dbSNP:rs63750301)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712, ECO:0000269|PubMed:9521423" FT /id="VAR_006444" FT VARIANT 266 FT /note="G -> S (in AD3; nearly abolishes protease activity FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs121917807)" FT /evidence="ECO:0000269|PubMed:11920851, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016219" FT VARIANT 267 FT /note="P -> S (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751229)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7550356" FT /id="VAR_006445" FT VARIANT 269 FT /note="R -> G (in AD3; decreased protease activity with FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751019)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_006447" FT VARIANT 269 FT /note="R -> H (in AD3; dbSNP:rs63750900)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_006448" FT VARIANT 271 FT /note="L -> V (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750886)" FT /evidence="ECO:0000269|PubMed:12493737, FT ECO:0000269|PubMed:27930341" FT /id="VAR_016220" FT VARIANT 274 FT /note="T -> R (in AD3; uncertain significance; abolishes FT protease activity with APP; dbSNP:rs63750284)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075271" FT VARIANT 275 FT /note="A -> V (in AD3; uncertain significance; reduced FT protease activity with APP resulting in reduced amyloid- FT beta 40 levels but no relevant changes in amyloid-beta 42/ FT amyloid-beta 40 ratio; dbSNP:rs1555355869)" FT /evidence="ECO:0000269|PubMed:24582897, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081251" FT VARIANT 278 FT /note="R -> I (in AD3; atypical phenotype presenting as FT language impairment, impaired frontal executive function FT and relative preservation of memory; severe decrease of APP FT and Notch proteolysis; dbSNP:rs63749891)" FT /evidence="ECO:0000269|PubMed:15534260, FT ECO:0000269|PubMed:23843529" FT /id="VAR_081252" FT VARIANT 278 FT /note="R -> T (in AD3; dbSNP:rs63749891)" FT /evidence="ECO:0000269|PubMed:9172170" FT /id="VAR_006449" FT VARIANT 280 FT /note="E -> A (in AD3; strong deposition of amyloid-beta 42 FT is observed in brain regions of AD3 patients; decreased FT protease activity with APP resulting in altered amyloid- FT beta production and increased amyloid-beta 42/amyloid-beta FT 40 ratio; decreased activity for Notch1 cleavage; FT dbSNP:rs63750231)" FT /evidence="ECO:0000269|PubMed:11568920, FT ECO:0000269|PubMed:22461631, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:28269784, ECO:0000269|PubMed:7550356, FT ECO:0000269|PubMed:8837617, ECO:0000269|PubMed:9298817" FT /id="VAR_006450" FT VARIANT 280 FT /note="E -> G (in AD3; some AD3 patients manifest spastic FT paraparesis and unusual amyloid plaques with prominent FT amyloid angiopathy on brain biopsy; decreased protease FT activity with APP; increased amyloid-beta 42/amyloid-beta FT 40 ratio; impaired ability to cleave Ephb2/CTF1; FT dbSNP:rs63750231)" FT /evidence="ECO:0000269|PubMed:12370477, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7550356" FT /id="VAR_006451" FT VARIANT 282 FT /note="L -> R (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750050)" FT /evidence="ECO:0000269|PubMed:10533070, FT ECO:0000269|PubMed:27930341" FT /id="VAR_009212" FT VARIANT 282 FT /note="L -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63749937)" FT /evidence="ECO:0000269|PubMed:11701593, FT ECO:0000269|PubMed:15122701, ECO:0000269|PubMed:16752394" FT /id="VAR_081253" FT VARIANT 285 FT /note="A -> V (in AD3; slightly decreased protease activity FT with APP and slightly decreased amyloid-beta 42/amyloid- FT beta 40 ratio; dbSNP:rs63751139)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7651536" FT /id="VAR_006452" FT VARIANT 286 FT /note="L -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63751235)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7596406" FT /id="VAR_006453" FT VARIANT 289 FT /note="S -> C (in AD3)" FT /evidence="ECO:0000269|PubMed:8875251" FT /id="VAR_010127" FT VARIANT 311 FT /note="K -> R (found in patients with late-onset Alzheimer FT disease; uncertain significance; results in altered FT amyloid-beta production and increased amyloid-beta 42/ FT amyloid-beta 40 ratio; dbSNP:rs115865530)" FT /evidence="ECO:0000269|PubMed:28269784" FT /id="VAR_081254" FT VARIANT 315 FT /note="Y -> C (found in a renal cell carcinoma sample; FT somatic mutation)" FT /evidence="ECO:0000269|PubMed:21248752" FT /id="VAR_064747" FT VARIANT 318 FT /note="E -> G (in dbSNP:rs17125721)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:10533070, ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:11568920, FT ECO:0000269|PubMed:12552037, ECO:0000269|PubMed:18485326, FT ECO:0000269|PubMed:9384602, ECO:0000269|PubMed:9851443, FT ECO:0000269|PubMed:9851450, ECO:0000269|PubMed:9915968" FT /id="VAR_006454" FT VARIANT 333 FT /note="D -> G (in CMD1U; results in slightly decreased FT protease activity with APP and slightly decreased amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs121917809)" FT /evidence="ECO:0000269|PubMed:17186461, FT ECO:0000269|PubMed:27930341" FT /id="VAR_064902" FT VARIANT 352 FT /note="R -> RR (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075272" FT VARIANT 354 FT /note="T -> I (in AD3; uncertain significance; results in FT decreased protease activity with APP and decreased amyloid- FT beta 42/amyloid-beta 40 ratio; dbSNP:rs63751164)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075273" FT VARIANT 358 FT /note="R -> Q (in AD3; uncertain significance; results in FT altered amyloid-beta production and increased amyloid-beta FT 42/amyloid-beta 40 ratio; dbSNP:rs63751174)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075274" FT VARIANT 365 FT /note="S -> Y (in AD3; uncertain significance; FT dbSNP:rs63750941)" FT /evidence="ECO:0000269|PubMed:11524469" FT /id="VAR_075275" FT VARIANT 377 FT /note="R -> M (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:12552037" FT /id="VAR_081255" FT VARIANT 378 FT /note="G -> E (in AD3; decreased protease activity with FT APP; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio)" FT /evidence="ECO:0000269|PubMed:10200054, FT ECO:0000269|PubMed:27930341" FT /id="VAR_006455" FT VARIANT 378 FT /note="G -> V (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750323)" FT /evidence="ECO:0000269|PubMed:12552037, FT ECO:0000269|PubMed:27073747, ECO:0000269|PubMed:27930341" FT /id="VAR_081256" FT VARIANT 381 FT /note="L -> F (in AD3; dbSNP:rs63750687)" FT /evidence="ECO:0000269|PubMed:24121961" FT /id="VAR_081257" FT VARIANT 381 FT /note="L -> V (in AD3; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; dbSNP:rs63750687)" FT /evidence="ECO:0000269|PubMed:19797784, FT ECO:0000269|PubMed:27930341" FT /id="VAR_081258" FT VARIANT 384 FT /note="G -> A (in AD3; results in reduced APP and Notch FT proteolysis; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750646)" FT /evidence="ECO:0000269|PubMed:16752394, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634711" FT /id="VAR_006456" FT VARIANT 390 FT /note="S -> I (in AD3; abolishes protease activity with FT APP; dbSNP:rs63750883)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010128" FT VARIANT 392 FT /note="L -> V (in AD3; results in reduced APP and Notch FT proteolysis; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63751416)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:8634712" FT /id="VAR_006457" FT VARIANT 394 FT /note="G -> V (in AD3; uncertain significance; abolishes FT protease activity with APP; dbSNP:rs63750929)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075276" FT VARIANT 396 FT /note="A -> T (in AD3; uncertain significance; decreased FT protease activity with APP; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio)" FT /evidence="ECO:0000269|PubMed:27930341" FT /id="VAR_070026" FT VARIANT 405 FT /note="N -> S (in AD3; uncertain significance; decreased FT protease activity with APP; dbSNP:rs63751254)" FT /evidence="ECO:0000269|PubMed:10644793, FT ECO:0000269|PubMed:27930341" FT /id="VAR_010129" FT VARIANT 408 FT /note="I -> T (in AD3; dbSNP:rs906454643)" FT /evidence="ECO:0000269|PubMed:26549787" FT /id="VAR_075277" FT VARIANT 409 FT /note="A -> T (in AD3; uncertain significance; decreased FT protease activity with APP; dbSNP:rs63750227)" FT /evidence="ECO:0000269|PubMed:10533070, FT ECO:0000269|PubMed:27930341" FT /id="VAR_009213" FT VARIANT 410 FT /note="C -> Y (in AD3; results in reduced APP and Notch FT proteolysis; dbSNP:rs661)" FT /evidence="ECO:0000269|PubMed:10441572, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:8634712, ECO:0000269|PubMed:9521423" FT /id="VAR_006458" FT VARIANT 417 FT /note="G -> A (in AD3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:30180983" FT /id="VAR_081259" FT VARIANT 418 FT /note="L -> F (in AD3; uncertain significance; nearly FT abolishes protease activity with APP; dbSNP:rs63751316)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075278" FT VARIANT 426 FT /note="A -> P (in AD3; uncertain significance; slightly FT decreased protease activity with APP; dbSNP:rs63751223)" FT /evidence="ECO:0000269|PubMed:27930341, FT ECO:0000269|PubMed:9521423" FT /id="VAR_006459" FT VARIANT 431 FT /note="A -> E (in AD3; decreased protease activity with FT APP; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63750083)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:16628450, ECO:0000269|PubMed:16897084, FT ECO:0000269|PubMed:27930341, ECO:0000269|Ref.95" FT /id="VAR_025605" FT VARIANT 435 FT /note="L -> F (in AD3; with unusual amyloid cotton wool FT plaques; almost abolishes gamma-secretase activity; no FT endoproteolytic cleavage; no APP nor NOTCH1 processing; no FT detectable amyloid-beta; dbSNP:rs63750001)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:20460383, FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341" FT /id="VAR_075280" FT VARIANT 436 FT /note="P -> Q (in AD3; severe decrease of protease activity FT with APP; dbSNP:rs121917808)" FT /evidence="ECO:0000269|PubMed:22529981, FT ECO:0000269|PubMed:9831473" FT /id="VAR_006460" FT VARIANT 436 FT /note="P -> S (in AD3; partially abolishes gamma-secretase FT activity; results in altered amyloid-beta production and FT increased amyloid-beta 42/amyloid-beta 40 ratio; FT dbSNP:rs63749925)" FT /evidence="ECO:0000269|PubMed:10090481, FT ECO:0000269|PubMed:21248752, ECO:0000269|PubMed:27930341" FT /id="VAR_008141" FT VARIANT 439 FT /note="I -> V (in AD3; uncertain significance; no FT significant change of protease activity with APP; FT dbSNP:rs63750249)" FT /evidence="ECO:0000269|PubMed:11524469, FT ECO:0000269|PubMed:27930341" FT /id="VAR_075282" FT MUTAGEN 66..72 FT /note="Missing: No effect on interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 76..77 FT /note="KY->AA: No effect on interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 82..83 FT /note="VI->EE: Loss of interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 82 FT /note="V->K,E: Loss of interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 84..85 FT /note="ML->EE: Loss of interaction with GFAP." FT /evidence="ECO:0000269|PubMed:12058025" FT MUTAGEN 99 FT /note="T->A: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 105 FT /note="F->I: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 108 FT /note="R->Q: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 112 FT /note="Q->C: Formation of an artifactual disulfide bond FT with a substrate protein." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 113 FT /note="L->Q: Severe decrease of protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 117 FT /note="P->A: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 123 FT /note="E->K: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 131 FT /note="H->R: Severe decrease of protease activity with FT APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 136 FT /note="A->G: Decreased protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 143 FT /note="I->V: Increased amyloid-beta 42/amyloid-beta 40 FT ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 150 FT /note="L->P: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 165 FT /note="W->G: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 168 FT /note="I->T: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 176 FT /note="F->L: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 184 FT /note="E->G: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 202 FT /note="I->F: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 212 FT /note="S->Y: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 214 FT /note="H->D: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 219 FT /note="L->F: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 223 FT /note="Q->R: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 226 FT /note="L->F: Increases protease activity with APP." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 230 FT /note="S->I: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 238 FT /note="I->M: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 239 FT /note="K->N: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 245 FT /note="T->P: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 248 FT /note="L->R: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 256 FT /note="Y->F: Alters gamma-secretase cleavage specificity. FT Increased production of amyloid-beta protein 42. No effect FT on enzymatic activity." FT /evidence="ECO:0000269|PubMed:15341515" FT MUTAGEN 256 FT /note="Y->S: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 257 FT /note="D->A: Loss of endoproteolytic cleavage. Severe FT decrease of protease activity with APP. Reduces production FT of amyloid-beta. Reduces production of NICD in NOTCH1 FT processing. Impaired ability to cleave Ephb2/CTF1." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:15341515, FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:22529981" FT MUTAGEN 257 FT /note="D->E: Abolishes gamma-secretase activity. Reduces FT production of amyloid-beta in APP processing. Accumulation FT of full-length PS1. Loss of binding of transition state FT analog gamma-secretase inhibitor." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:15341515" FT MUTAGEN 272 FT /note="V->A: Increased amyloid-beta 42/amyloid-beta 40 FT ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 273 FT /note="E->A: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 278 FT /note="R->K: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 284 FT /note="P->S: No significant change of protease activity FT with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 286 FT /note="L->A,E,P,Q,R,W: Increases production of amyloid-beta FT in APP processing." FT /evidence="ECO:0000269|PubMed:10811883" FT MUTAGEN 286 FT /note="L->E,R: Reduces production of NICD in NOTCH1 FT processing." FT /evidence="ECO:0000269|PubMed:10811883" FT MUTAGEN 288..290 FT /note="Missing: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 291 FT /note="T->P: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 292 FT /note="M->D: Loss of endoproteolytic cleavage." FT /evidence="ECO:0000269|PubMed:10545183" FT MUTAGEN 310 FT /note="S->A: Abolishes PKA-mediated phosphorylation; no FT effect on caspase-mediated cleavage." FT /evidence="ECO:0000269|PubMed:14576165" FT MUTAGEN 345 FT /note="D->N: Abolishes caspase cleavage." FT /evidence="ECO:0000269|PubMed:9485372" FT MUTAGEN 346 FT /note="S->A: Abolishes PKC-mediated phosphorylation; no FT effect on PKA-mediated phosphorylation." FT /evidence="ECO:0000269|PubMed:14576165" FT MUTAGEN 346 FT /note="S->E: Inhibits caspase-mediated cleavage. Modulates FT progression of apoptosis." FT /evidence="ECO:0000269|PubMed:14576165" FT MUTAGEN 352 FT /note="R->C: Decreased protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 365 FT /note="S->A: Slightly increased protease activity with FT APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 373 FT /note="D->N: No effect on caspase cleavage." FT /evidence="ECO:0000269|PubMed:9485372" FT MUTAGEN 377..381 FT /note="Missing: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 377 FT /note="R->W: Nearly abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 385 FT /note="D->A: Loss of endoproteolytic cleavage. Severe FT decrease of protease activity with APP. Reduces production FT of amyloid-beta. Loss of NOTCH1 cleavage. Disassembly of FT the N-cadherin/PS1 complex at the cell surface. Impairs FT CDH2 processing." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347, FT ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:22529981, FT ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, FT ECO:0000269|PubMed:9485372" FT MUTAGEN 385 FT /note="D->E: Abolishes gamma-secretase activity. Reduces FT production of amyloid-beta in APP processing. Accumulation FT of full-length PS1. Loss of binding of transition state FT analog gamma-secretase inhibitor." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347, FT ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:9485372" FT MUTAGEN 385 FT /note="D->N: No effect on caspase cleavage." FT /evidence="ECO:0000269|PubMed:10206644, FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347, FT ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:9485372" FT MUTAGEN 386 FT /note="F->S: Nearly abolishes protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 389 FT /note="Y->F: Alters gamma-secretase cleavage specificity. FT Increased production of amyloid-beta protein 42. No effect FT on enzymatic activity." FT /evidence="ECO:0000269|PubMed:15341515" FT MUTAGEN 391 FT /note="V->F: Decreased protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 412 FT /note="V->I: Abolishes protease activity with APP." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 420 FT /note="L->R: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT MUTAGEN 424 FT /note="L->V: Increases protease activity with APP." FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 432..434 FT /note="Missing: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 432 FT /note="L->P: Loss of NOTCH1 and APP C83 cleavage." FT /evidence="ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874" FT MUTAGEN 433 FT /note="P->A: No effect on endoproteolytic cleavage. No FT effect on APP nor NOTCH1 processing. Slightly increased FT amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 433 FT /note="P->D,F,L,N,V: No endoproteolytic cleavage; no APP, FT nor NOTCH1 processing. No detectable amyloid-beta." FT /evidence="ECO:0000269|PubMed:16305624, FT ECO:0000269|PubMed:20460383" FT MUTAGEN 433 FT /note="P->G: Very little endoproteolysis. Little APP FT processing. No NOTCH1 processing. Very low levels amyloid- FT beta protein 40 and no detectable amyloid-beta protein 42." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 434 FT /note="A->C: Some loss of endoproteolytic cleavage. Some FT loss of APP and NOTCH1 processing. 6 to 13-fold increase in FT amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624, FT ECO:0000269|PubMed:27930341" FT MUTAGEN 434 FT /note="A->D,I,L,V: No endoproteolytic cleavage. No APP nor FT NOTCH1 processing. No detectable amyloid-beta." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 434 FT /note="A->G: No effect on endoproteolytic cleavage. No FT effect on APP nor NOTCH1 processing. Reduced amyloid-beta FT protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->A: No effect on endoproteolytic cleavage. No FT effect on APP processing. Impaired NOTCH1 processing. FT Greatly reduced amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->G: Greatly reduced endoproteolytic cleavage. Very FT little APP and NOTCH1 processing. Very low levels of FT amyloid-beta protein 40 and no detectable amyloid-beta FT protein 42." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->I: No effect on endoproteolytic cleavage. No FT effect on APP nor NOTCH1 processing." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 435 FT /note="L->R: No endoproteolytic cleavage; no APP, nor FT NOTCH1 processing. No detectable amyloid-beta." FT /evidence="ECO:0000269|PubMed:20460383" FT MUTAGEN 435 FT /note="L->V: No effect on endoproteolytic cleavage. No FT effect on APP processing. Impaired NOTCH1 processing. Some FT increase in amyloid-beta protein 42/40 ratio." FT /evidence="ECO:0000269|PubMed:16305624" FT MUTAGEN 437 FT /note="I->V: Decreased protease activity with APP. FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro." FT /evidence="ECO:0000269|PubMed:27930341" FT CONFLICT 128 FT /note="R -> G (in Ref. 7; AAL16811)" FT /evidence="ECO:0000305" FT STRAND 77..80 FT /evidence="ECO:0007829|PDB:6LR4" FT HELIX 83..102 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 105..107 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 114..116 FT /evidence="ECO:0007829|PDB:8X52" FT STRAND 120..123 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 125..155 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 159..175 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 177..188 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 195..214 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 219..240 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 243..262 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 263..266 FT /evidence="ECO:0007829|PDB:6IDF" FT HELIX 267..277 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 278..280 FT /evidence="ECO:0007829|PDB:6IDF" FT TURN 284..286 FT /evidence="ECO:0007829|PDB:8KCU" FT STRAND 287..289 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 293..299 FT /evidence="ECO:0007829|PDB:2KR6" FT STRAND 341..345 FT /evidence="ECO:0007829|PDB:2KR6" FT HELIX 356..368 FT /evidence="ECO:0007829|PDB:2KR6" FT STRAND 380..382 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 383..398 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 400..402 FT /evidence="ECO:0007829|PDB:8OQY" FT HELIX 403..428 FT /evidence="ECO:0007829|PDB:8KCS" FT STRAND 432..434 FT /evidence="ECO:0007829|PDB:6IDF" FT HELIX 435..451 FT /evidence="ECO:0007829|PDB:8KCS" FT HELIX 454..463 FT /evidence="ECO:0007829|PDB:8KCS" SQ SEQUENCE 467 AA; 52668 MW; 5E0F451EF82BCF20 CRC64; MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL SNGRPQGNSR QVVEQDEEED EELTLKYGAK HVIMLFVPVT LCMVVVVATI KSVSFYTRKD GQLIYTPFTE DTETVGQRAL HSILNAAIMI SVIVVMTILL VVLYKYRCYK VIHAWLIISS LLLLFFFSFI YLGEVFKTYN VAVDYITVAL LIWNFGVVGM ISIHWKGPLR LQQAYLIMIS ALMALVFIKY LPEWTAWLIL AVISVYDLVA VLCPKGPLRM LVETAQERNE TLFPALIYSS TMVWLVNMAE GDPEAQRRVS KNSKYNAEST ERESQDTVAE NDDGGFSEEW EAQRDSHLGP HRSTPESRAA VQELSSSILA GEDPEERGVK LGLGDFIFYS VLVGKASATA SGDWNTTIAC FVAILIGLCL TLLLLAIFKK ALPALPISIT FGLVFYFATD YLVQPFMDQL AFHQFYI // ID PSN2_HUMAN Reviewed; 448 AA. AC P49810; A8K8D4; B1AP21; Q96P32; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1996, sequence version 1. DT 28-JAN-2026, entry version 243. DE RecName: Full=Presenilin-2 {ECO:0000303|PubMed:10497236}; DE Short=PS-2; DE EC=3.4.23.- {ECO:0000269|PubMed:10497236}; DE AltName: Full=AD3LP; DE AltName: Full=AD5; DE AltName: Full=E5-1; DE AltName: Full=STM-2; DE Contains: DE RecName: Full=Presenilin-2 NTF subunit {ECO:0000305|PubMed:10652302}; DE Contains: DE RecName: Full=Presenilin-2 CTF subunit {ECO:0000305|PubMed:10497236, ECO:0000305|PubMed:10652302}; GN Name=PSEN2 {ECO:0000312|HGNC:HGNC:9509}; GN Synonyms=AD4, PS2, PSNL2, STM2 {ECO:0000303|PubMed:8661049}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT AD4 ILE-141. RX PubMed=7638622; DOI=10.1126/science.7638622; RA Levy-Lahad E., Wasco W., Poorkaj P., Romano D.M., Oshima J., RA Pettingell W.H. Jr., Yu C.-E., Jondro P.D., Schmidt S.D., Wang K., RA Crowley A.C., Fu Y.-H., Guenette S.Y., Galas D., Nemens E., Wijsman E.M., RA Bird T.D., Schellenberg G.D., Tanzi R.E.; RT "Candidate gene for the chromosome 1 familial Alzheimer's disease locus."; RL Science 269:973-977(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS AD4 ILE-141 AND VAL-239. RC TISSUE=Brain, and Colon; RX PubMed=7651536; DOI=10.1038/376775a0; RA Rogaev E.I., Sherrington R., Rogaeva E.A., Levesque G., Ikeda M., Liang Y., RA Chi H., Lin C., Holman K., Tsuda T., Mar L., Sorbi S., Nacmias B., RA Piacentini S., Amaducci L., Chumakov I., Cohen D., Lannfelt L., RA Fraser P.E., Rommens J.M., St George-Hyslop P.H.; RT "Familial Alzheimer's disease in kindreds with missense mutations in a gene RT on chromosome 1 related to the Alzheimer's disease type 3 gene."; RL Nature 376:775-778(1995). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=8661049; DOI=10.1006/geno.1996.0266; RA Levy-Lahad E., Poorkaj P., Wang K., Fu Y.H., Oshima J., Mulligan J., RA Schellenberg G.D.; RT "Genomic structure and expression of STM2, the chromosome 1 familial RT Alzheimer disease gene."; RL Genomics 34:198-204(1996). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Testis; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Muscle; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-361. RX PubMed=8618867; DOI=10.1073/pnas.92.26.12180; RA Li J., Ma J., Potter H.; RT "Identification and expression analysis of a potential familial Alzheimer RT disease gene on chromosome 1 related to AD3."; RL Proc. Natl. Acad. Sci. U.S.A. 92:12180-12184(1995). RN [10] RP NUCLEOTIDE SEQUENCE OF 1-390. RA Xu Y., Hu X., Zhou Y., Peng X., Yuan J., Qiang B.; RL Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases. RN [11] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=8574969; DOI=10.1038/nm0296-224; RA Kovacs D.M., Fausett H.J., Page K.J., Kim T.-W., Moir R.D., Merriam D.E., RA Hollister R.D., Hallmark O.G., Mancini R., Felsenstein K.M., Hyman B.T., RA Tanzi R.E., Wasco W.; RT "Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and RT localization to intracellular membranes in mammalian cells."; RL Nat. Med. 2:224-229(1996). RN [12] RP INTERACTION WITH FLNA AND FLNB. RX PubMed=9437013; DOI=10.1523/jneurosci.18-03-00914.1998; RA Zhang W., Han S.W., McKeel D.W., Goate A., Wu J.Y.; RT "Interaction of presenilins with the filamin family of actin-binding RT proteins."; RL J. Neurosci. 18:914-922(1998). RN [13] RP FUNCTION, PROTEOLYTIC CLEAVAGE, ACTIVE SITE ASP-366, AND MUTAGENESIS OF RP ASP-366. RX PubMed=10497236; DOI=10.1074/jbc.274.40.28669; RA Steiner H., Duff K., Capell A., Romig H., Grim M.G., Lincoln S., Hardy J., RA Yu X., Picciano M., Fechteler K., Citron M., Kopan R., Pesold B., Keck S., RA Baader M., Tomita T., Iwatsubo T., Baumeister R., Haass C.; RT "A loss of function mutation of presenilin-2 interferes with amyloid beta- RT peptide production and notch signaling."; RL J. Biol. Chem. 274:28669-28673(1999). RN [14] RP FUNCTION, PROTEOLYTIC CLEAVAGE, ACTIVE SITES ASP-263 AND ASP-366, AND RP MUTAGENESIS OF ASP-263 AND ASP-366. RX PubMed=10652302; DOI=10.1074/jbc.275.5.3173; RA Kimberly W.T., Xia W., Rahmati T., Wolfe M.S., Selkoe D.J.; RT "The transmembrane aspartates in presenilin 1 and 2 are obligatory for RT gamma-secretase activity and amyloid beta-protein generation."; RL J. Biol. Chem. 275:3173-3178(2000). RN [15] RP INTERACTION WITH DOCK3. RX PubMed=10854253; DOI=10.1046/j.1471-4159.2000.0750109.x; RA Kashiwa A., Yoshida H., Lee S., Paladino T., Liu Y., Chen Q., Dargusch R., RA Schubert D., Kimura H.; RT "Isolation and characterization of novel presenilin binding protein."; RL J. Neurochem. 75:109-116(2000). RN [16] RP INTERACTION WITH PARL. RX PubMed=12214059; DOI=10.3233/jad-2001-3203; RA Pellegrini L., Passer B.J., Canelles M., Lefterov I., Ganjei J.K., RA Fowlkes B.J., Koonin E.V., D'Adamio L.; RT "PAMP and PARL, two novel putative metalloproteases interacting with the RT COOH-terminus of presenilin-1 and -2."; RL J. Alzheimers Dis. 3:181-190(2001). RN [17] RP INTERACTION WITH HERPUD1. RX PubMed=11799129; DOI=10.1074/jbc.m112372200; RA Sai X., Kawamura Y., Kokame K., Yamaguchi H., Shiraishi H., Suzuki R., RA Suzuki T., Kawaichi M., Miyata T., Kitamura T., De Strooper B., RA Yanagisawa K., Komano H.; RT "Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin- RT mediated generation of amyloid beta-protein."; RL J. Biol. Chem. 277:12915-12920(2002). RN [18] RP REVIEW ON VARIANTS. RX PubMed=9521418; RX DOI=10.1002/(sici)1098-1004(1998)11:3<183::aid-humu1>3.0.co;2-j; RA Cruts M., van Broeckhoven C.; RT "Presenilin mutations in Alzheimer's disease."; RL Hum. Mutat. 11:183-190(1998). RN [19] RP SUBUNIT, AND PROTEOLYTIC CLEAVAGE. RX PubMed=15274632; DOI=10.1021/bi0494976; RA Fraering P.C., Ye W., Strub J.-M., Dolios G., LaVoie M.J., RA Ostaszewski B.L., van Dorsselaer A., Wang R., Selkoe D.J., Wolfe M.S.; RT "Purification and characterization of the human gamma-secretase complex."; RL Biochemistry 43:9774-9789(2004). RN [20] RP FUNCTION, AND CHARACTERIZATION OF VARIANT AD4 ILE-141. RX PubMed=16959576; DOI=10.1016/j.cell.2006.06.059; RA Tu H., Nelson O., Bezprozvanny A., Wang Z., Lee S.F., Hao Y.H., RA Serneels L., De Strooper B., Yu G., Bezprozvanny I.; RT "Presenilins form ER Ca2+ leak channels, a function disrupted by familial RT Alzheimer's disease-linked mutations."; RL Cell 126:981-993(2006). RN [21] RP FUNCTION, AND CHARACTERIZATION OF VARIANT AD4 ILE-141. RX PubMed=16752394; DOI=10.1002/humu.20336; RA Kumar-Singh S., Theuns J., Van Broeck B., Pirici D., Vennekens K., RA Corsmit E., Cruts M., Dermaut B., Wang R., Van Broeckhoven C.; RT "Mean age-of-onset of familial alzheimer disease caused by presenilin RT mutations correlates with both increased Abeta42 and decreased Abeta40."; RL Hum. Mutat. 27:686-695(2006). RN [22] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [23] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [24] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-22 AND SER-25, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [25] RP FUNCTION, CHARACTERIZATION OF VARIANTS AD4 ARG-122 AND ILE-141, AND RP MUTAGENESIS OF ASP-366. RX PubMed=21285369; DOI=10.1073/pnas.1100735108; RA Zampese E., Fasolato C., Kipanyula M.J., Bortolozzi M., Pozzan T., RA Pizzo P.; RT "Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria RT interactions and Ca2+ cross-talk."; RL Proc. Natl. Acad. Sci. U.S.A. 108:2777-2782(2011). RN [26] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-22 AND SER-25, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [27] 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 [28] RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH AP1G1, MUTAGENESIS OF RP SER-7; SER-9; 16-GLU--MET-21 AND SER-19, PHOSPHORYLATION AT SER-19, TISSUE RP SPECIFICITY, VARIANTS AD4 PRO-122; ILE-141; VAL-239 AND ILE-239, AND RP CHARACTERIZATION OF VARIANTS AD4 PRO-122; ILE-141; VAL-239 AND ILE-239. RX PubMed=27293189; DOI=10.1016/j.cell.2016.05.020; RA Sannerud R., Esselens C., Ejsmont P., Mattera R., Rochin L., RA Tharkeshwar A.K., De Baets G., De Wever V., Habets R., Baert V., RA Vermeire W., Michiels C., Groot A.J., Wouters R., Dillen K., Vints K., RA Baatsen P., Munck S., Derua R., Waelkens E., Basi G.S., Mercken M., RA Vooijs M., Bollen M., Schymkowitz J., Rousseau F., Bonifacino J.S., RA Van Niel G., De Strooper B., Annaert W.; RT "Restricted Location of PSEN2/gamma-Secretase Determines Substrate RT Specificity and Generates an Intracellular Abeta Pool."; RL Cell 166:193-208(2016). RN [29] {ECO:0007744|PDB:7Y5X, ECO:0007744|PDB:7Y5Z} RP STRUCTURE BY ELECTRON MICROSCOPY (3.00 ANGSTROMS) IN COMPLEX WITH NCSTN; RP APH1A AND PSENEN, IDENTIFICATION OF GAMMA SECRETASE COMPLEX, AND FUNCTION. RX PubMed=36272978; DOI=10.1038/s41467-022-33817-5; RA Guo X., Wang Y., Zhou J., Jin C., Wang J., Jia B., Jing D., Yan C., Lei J., RA Zhou R., Shi Y.; RT "Molecular basis for isoform-selective inhibition of presenilin-1 by MRK- RT 560."; RL Nat. Commun. 13:6299-6299(2022). RN [30] RP VARIANT AD4 HIS-62. RX PubMed=9384602; DOI=10.1093/hmg/7.1.43; RA Cruts M., van Duijn C.M., Backhovens H., van den Broeck M., Wehnert A., RA Serneels S., Sherrington R., Hutton M., Hardy J., St George-Hyslop P.H., RA Hofman A., van Broeckhoven C.; RT "Estimation of the genetic contribution of presenilin-1 and -2 mutations in RT a population-based study of presenile Alzheimer disease."; RL Hum. Mol. Genet. 7:43-51(1998). RN [31] RP VARIANT AD4 ILE-148. RX PubMed=10732806; DOI=10.1007/s100480050044; RA Lao J.I., Beyer K., Fernandez-Novoa L., Cacabelos R.; RT "A novel mutation in the predicted TM2 domain of the presenilin 2 gene in RT Spanish patient with late-onset Alzheimer's disease."; RL Neurogenetics 1:293-296(1998). RN [32] RP VARIANTS AD4 PRO-122 AND ILE-239. RX PubMed=10631141; DOI=10.1086/302702; RA Finckh U., Mueller-Thomsen T., Mann U., Eggers C., Marksteiner J., RA Meins W., Binetti G., Alberici A., Hock C., Nitsch R.M., Gal A.; RT "High prevalence of pathogenic mutations in patients with early-onset RT dementia detected by sequence analyses of four different genes."; RL Am. J. Hum. Genet. 66:110-117(2000). RN [33] RP VARIANT AD4 ARG-122. RX PubMed=14681895; DOI=10.1002/ana.10760; RA Binetti G., Signorini S., Squitti R., Alberici A., Benussi L., Cassetta E., RA Frisoni G.B., Barbiero L., Feudatari E., Nicosia F., Testa C., Zanetti O., RA Gennarelli M., Perani D., Anchisi D., Ghidoni R., Rossini P.M.; RT "Atypical dementia associated with a novel presenilin-2 mutation."; RL Ann. Neurol. 54:832-836(2003). RN [34] RP VARIANT CMD1V LEU-130. RX PubMed=17186461; DOI=10.1086/509900; RA Li D., Parks S.B., Kushner J.D., Nauman D., Burgess D., Ludwigsen S., RA Partain J., Nixon R.R., Allen C.N., Irwin R.P., Jakobs P.M., Litt M., RA Hershberger R.E.; RT "Mutations of presenilin genes in dilated cardiomyopathy and heart RT failure."; RL Am. J. Hum. Genet. 79:1030-1039(2006). RN [35] RP VARIANT AD4 TRP-71. RX PubMed=21544564; DOI=10.1007/s00415-011-6066-1; RA Piscopo P., Talarico G., Malvezzi-Campeggi L., Crestini A., Rivabene R., RA Gasparini M., Tosto G., Vanacore N., Lenzi G.L., Bruno G., Confaloni A.; RT "Presenilin 2 mutation R71W in an Italian early-onset sporadic Alzheimer's RT disease case."; RL J. Neurol. 258:2043-2047(2011). RN [36] RP VARIANTS AD4 HIS-62; TRP-71 AND LEU-130. RX PubMed=22503161; DOI=10.1016/j.neurobiolaging.2012.02.020; RA Lohmann E., Guerreiro R.J., Erginel-Unaltuna N., Gurunlian N., Bilgic B., RA Gurvit H., Hanagasi H.A., Luu N., Emre M., Singleton A.; RT "Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish RT dementia patients."; RL Neurobiol. Aging 33:1850.E17-1850.E27(2012). RN [37] RP VARIANT AD4 LYS-126. RX PubMed=24844686; DOI=10.3233/jad-140399; RA Mueller U., Winter P., Bolender C., Nolte D.; RT "Previously unrecognized missense mutation E126K of PSEN2 segregates with RT early onset Alzheimer's disease in a family."; RL J. Alzheimers Dis. 42:109-113(2014). RN [38] RP VARIANT AD4 TYR-141. RX PubMed=24838186; DOI=10.1016/j.neurobiolaging.2014.04.011; RA Niu F., Yu S., Zhang Z., Yi X., Ye L., Tang W., Qiu C., Wen H., Sun Y., RA Gao J., Guo Y.; RT "Novel mutation in the PSEN2 gene (N141Y) associated with early-onset RT autosomal dominant Alzheimer's disease in a Chinese Han family."; RL Neurobiol. Aging 35:E1-E5(2014). CC -!- FUNCTION: Catalytic subunit of the gamma-secretase complex, an CC endoprotease complex that catalyzes the intramembrane cleavage of CC integral membrane proteins such as Notch receptors and APP (amyloid- CC beta precursor protein) (PubMed:10497236, PubMed:10652302, CC PubMed:16752394, PubMed:27293189, PubMed:36272978). Selectively cleaves CC late endosomal/lysosomal localized substrates and generates the CC prominent pool of intracellular amyloid beta that contains longer CC amyloid beta (PubMed:27293189). The holoprotein functions as a calcium- CC leak channel that allows the passive movement of calcium from CC endoplasmic reticulum to cytosol and is involved in calcium homeostasis CC (PubMed:16959576). Is a regulator of mitochondrion-endoplasmic CC reticulum membrane tethering and modulates calcium ions shuttling CC between ER and mitochondria (PubMed:21285369). CC {ECO:0000269|PubMed:10497236, ECO:0000269|PubMed:10652302, CC ECO:0000269|PubMed:16752394, ECO:0000269|PubMed:16959576, CC ECO:0000269|PubMed:21285369, ECO:0000269|PubMed:27293189, CC ECO:0000269|PubMed:36272978}. CC -!- SUBUNIT: Homodimer; predominantly heterodimer of a N-terminal (NTF) and CC a C-terminal (CTF) endoproteolytical fragment (PubMed:15274632). CC Component of the gamma-secretase complex, a complex composed of a CC presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A CC or APH1B) and PSENEN (PubMed:36272978). Such minimal complex is CC sufficient for secretase activity, although other components may exist CC (By similarity). Interacts with DOCK3 (PubMed:10854253). Interacts with CC HERPUD1, FLNA, FLNB and PARL (PubMed:11799129, PubMed:12214059, CC PubMed:9437013). Interacts with AP1G1; this interaction is CC phosphorylation dependent and directs PSEN2 via early endosome to late CC endosome/lysosome (PubMed:27293189). {ECO:0000250|UniProtKB:P49768, CC ECO:0000269|PubMed:10854253, ECO:0000269|PubMed:11799129, CC ECO:0000269|PubMed:12214059, ECO:0000269|PubMed:15274632, CC ECO:0000269|PubMed:27293189, ECO:0000269|PubMed:36272978, CC ECO:0000269|PubMed:9437013}. CC -!- INTERACTION: CC P49810; P54819: AK2; NbExp=3; IntAct=EBI-2010251, EBI-1056291; CC P49810; P05067: APP; NbExp=4; IntAct=EBI-2010251, EBI-77613; CC P49810; Q0P5N6: ARL16; NbExp=3; IntAct=EBI-2010251, EBI-10186132; CC P49810; Q16611: BAK1; NbExp=3; IntAct=EBI-2010251, EBI-519866; CC P49810; Q07817: BCL2L1; NbExp=3; IntAct=EBI-2010251, EBI-78035; CC P49810; P29466-3: CASP1; NbExp=3; IntAct=EBI-2010251, EBI-12248206; CC P49810; Q99828: CIB1; NbExp=3; IntAct=EBI-2010251, EBI-372594; CC P49810; Q86WV2: COX4I1; NbExp=3; IntAct=EBI-2010251, EBI-10260134; CC P49810; Q14204: DYNC1H1; NbExp=3; IntAct=EBI-2010251, EBI-356015; CC P49810; Q9BQ95: ECSIT; NbExp=4; IntAct=EBI-2010251, EBI-712452; CC P49810; O00472: ELL2; NbExp=3; IntAct=EBI-2010251, EBI-395274; CC P49810; Q14192: FHL2; NbExp=3; IntAct=EBI-2010251, EBI-701903; CC P49810; P21333: FLNA; NbExp=2; IntAct=EBI-2010251, EBI-350432; CC P49810; O75369: FLNB; NbExp=2; IntAct=EBI-2010251, EBI-352089; CC P49810; Q3SYB3: FOXD4L6; NbExp=3; IntAct=EBI-2010251, EBI-6425864; CC P49810; P02792: FTL; NbExp=3; IntAct=EBI-2010251, EBI-713279; CC P49810; P68431: H3C12; NbExp=3; IntAct=EBI-2010251, EBI-79722; CC P49810; Q8WVV9-3: HNRNPLL; NbExp=3; IntAct=EBI-2010251, EBI-25845242; CC P49810; Q8TDB4: MGARP; NbExp=3; IntAct=EBI-2010251, EBI-4397720; CC P49810; O94851: MICAL2; NbExp=3; IntAct=EBI-2010251, EBI-2804835; CC P49810; A4FUJ8: MKL1; NbExp=3; IntAct=EBI-2010251, EBI-21250407; CC P49810; P41218: MNDA; NbExp=3; IntAct=EBI-2010251, EBI-2829677; CC P49810; Q96HT8: MRFAP1L1; NbExp=3; IntAct=EBI-2010251, EBI-748896; CC P49810; O76041: NEBL; NbExp=3; IntAct=EBI-2010251, EBI-2880203; CC P49810; Q53EL6: PDCD4; NbExp=3; IntAct=EBI-2010251, EBI-935824; CC P49810; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-2010251, EBI-716063; CC P49810; P27986-2: PIK3R1; NbExp=3; IntAct=EBI-2010251, EBI-9090282; CC P49810; Q99496: RNF2; NbExp=3; IntAct=EBI-2010251, EBI-722416; CC P49810; Q8N488: RYBP; NbExp=3; IntAct=EBI-2010251, EBI-752324; CC P49810; Q2NKQ1-4: SGSM1; NbExp=3; IntAct=EBI-2010251, EBI-10182463; CC P49810; Q9GZS3: SKIC8; NbExp=3; IntAct=EBI-2010251, EBI-358545; CC P49810; Q9NSD5-3: SLC6A13; NbExp=3; IntAct=EBI-2010251, EBI-25831241; CC P49810; O95416: SOX14; NbExp=3; IntAct=EBI-2010251, EBI-9087806; CC P49810; Q3SY56: SP6; NbExp=3; IntAct=EBI-2010251, EBI-11175533; CC P49810; P30626: SRI; NbExp=2; IntAct=EBI-2010251, EBI-750459; CC P49810; Q9BSL1: UBAC1; NbExp=3; IntAct=EBI-2010251, EBI-749370; CC P49810; Q9UMX0: UBQLN1; NbExp=3; IntAct=EBI-2010251, EBI-741480; CC P49810; Q96NC0: ZMAT2; NbExp=3; IntAct=EBI-2010251, EBI-2682299; CC P49810; Q8N895: ZNF366; NbExp=3; IntAct=EBI-2010251, EBI-2813661; CC P49810; Q8NBB4-2: ZSCAN1; NbExp=3; IntAct=EBI-2010251, EBI-12021938; CC P49810; Q2QGD7: ZXDC; NbExp=3; IntAct=EBI-2010251, EBI-1538838; CC P49810; P62493: RAB11A; Xeno; NbExp=2; IntAct=EBI-2010251, EBI-7030357; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:8574969}; Multi-pass membrane protein CC {ECO:0000255}. Golgi apparatus membrane {ECO:0000269|PubMed:8574969}; CC Multi-pass membrane protein {ECO:0000255}. Late endosome membrane CC {ECO:0000269|PubMed:27293189}. Lysosome membrane CC {ECO:0000269|PubMed:27293189}. Note=Late endosome/lysosome localization CC is dependent of the phosphorylation-mediated interaction with the AP1G1 CC (PubMed:27293189). Also highly enriched in mitochondria-associated CC endoplasmic reticulum membrane contact site (By similarity). CC {ECO:0000250|UniProtKB:Q61144, ECO:0000269|PubMed:27293189}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=P49810-1; Sequence=Displayed; CC Name=2; CC IsoId=P49810-2; Sequence=VSP_005194; CC Name=3; CC IsoId=P49810-3; Sequence=VSP_043648; CC -!- TISSUE SPECIFICITY: [Isoform 1]: Expressed in the placenta, skeletal CC muscle and heart (PubMed:8574969). Expressed in the somatodendritic CC compartment of hippocampal neurons (PubMed:27293189). CC {ECO:0000269|PubMed:27293189, ECO:0000269|PubMed:8574969}. CC -!- TISSUE SPECIFICITY: [Isoform 2]: Expressed in the heart, brain, CC placenta, liver, skeletal muscle and kidney. CC {ECO:0000269|PubMed:8574969}. CC -!- DOMAIN: The PAL motif is required for normal active site conformation. CC {ECO:0000250|UniProtKB:P49768}. CC -!- PTM: Heterogeneous proteolytic processing generates N-terminal and C- CC terminal fragments. {ECO:0000269|PubMed:10497236, CC ECO:0000269|PubMed:10652302, ECO:0000269|PubMed:36272978}. CC -!- PTM: Phosphorylated on serine residues (PubMed:27293189). CC Phosphorylation at Ser-19 affects PSEN2 sorting (PubMed:27293189). CC {ECO:0000269|PubMed:27293189}. CC -!- DISEASE: Alzheimer disease 4 (AD4) [MIM:606889]: A familial early-onset CC form of Alzheimer disease. Alzheimer disease is a neurodegenerative CC disorder characterized by progressive dementia, loss of cognitive CC abilities, and deposition of fibrillar amyloid proteins as CC intraneuronal neurofibrillary tangles, extracellular amyloid plaques CC and vascular amyloid deposits. The major constituents of these plaques CC are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, CC that are produced by the proteolysis of the transmembrane APP protein. CC The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved CC products, such as C31, are also implicated in neuronal death. CC {ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10732806, CC ECO:0000269|PubMed:14681895, ECO:0000269|PubMed:16752394, CC ECO:0000269|PubMed:16959576, ECO:0000269|PubMed:21285369, CC ECO:0000269|PubMed:21544564, ECO:0000269|PubMed:22503161, CC ECO:0000269|PubMed:24838186, ECO:0000269|PubMed:24844686, CC ECO:0000269|PubMed:27293189, ECO:0000269|PubMed:7638622, CC ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:9384602}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Cardiomyopathy, dilated, 1V (CMD1V) [MIM:613697]: A disorder CC characterized by ventricular dilation and impaired systolic function, CC resulting in congestive heart failure and arrhythmia. Patients are at CC risk of premature death. {ECO:0000269|PubMed:17186461}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the peptidase A22A family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAC50290.1; Type=Frameshift; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Alzheimer Research Forum; Note=Presenilins CC mutations; CC URL="https://www.alzforum.org/mutations/psen-2"; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/41883/PSEN2"; 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; L43964; AAB59557.1; -; mRNA. DR EMBL; L44577; AAC42012.1; -; mRNA. DR EMBL; U50871; AAB50054.1; -; Genomic_DNA. DR EMBL; BT006984; AAP35630.1; -; mRNA. DR EMBL; AK292299; BAF84988.1; -; mRNA. DR EMBL; AL391628; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471098; EAW69798.1; -; Genomic_DNA. DR EMBL; CH471098; EAW69800.1; -; Genomic_DNA. DR EMBL; BC006365; AAH06365.1; -; mRNA. DR EMBL; U34349; AAC50290.1; ALT_FRAME; mRNA. DR EMBL; AF416718; AAL16812.1; -; mRNA. DR CCDS; CCDS1556.1; -. [P49810-1] DR CCDS; CCDS44324.1; -. [P49810-3] DR PIR; A56993; A56993. DR PIR; I39174; I39174. DR RefSeq; NP_000438.2; NM_000447.3. [P49810-1] DR RefSeq; NP_001424466.1; NM_001437537.1. [P49810-1] DR RefSeq; NP_036618.2; NM_012486.3. [P49810-3] DR RefSeq; XP_016857324.1; XM_017001835.2. [P49810-1] DR RefSeq; XP_016857325.1; XM_017001836.2. [P49810-3] DR RefSeq; XP_047281552.1; XM_047425596.1. [P49810-1] DR RefSeq; XP_047281553.1; XM_047425597.1. [P49810-3] DR RefSeq; XP_047281557.1; XM_047425601.1. [P49810-3] DR RefSeq; XP_054193714.1; XM_054337739.1. [P49810-1] DR RefSeq; XP_054193715.1; XM_054337740.1. [P49810-3] DR RefSeq; XP_054193716.1; XM_054337741.1. [P49810-3] DR PDB; 7Y5X; EM; 3.00 A; B=1-448. DR PDB; 7Y5Z; EM; 3.40 A; B=1-448. DR PDBsum; 7Y5X; -. DR PDBsum; 7Y5Z; -. DR AlphaFoldDB; P49810; -. DR EMDB; EMD-33628; -. DR EMDB; EMD-33629; -. DR PCDDB; P49810; -. DR SMR; P49810; -. DR BioGRID; 111643; 82. DR ComplexPortal; CPX-4231; Gamma-secretase complex, APH1A-PSEN2 variant. DR ComplexPortal; CPX-4232; Gamma-secretase complex, APH1B-PSEN2 variant. DR CORUM; P49810; -. DR FunCoup; P49810; 386. DR IntAct; P49810; 76. DR MINT; P49810; -. DR STRING; 9606.ENSP00000355747; -. DR BindingDB; P49810; -. DR ChEMBL; CHEMBL3708; -. DR DrugBank; DB16159; Esflurbiprofen. DR DrugBank; DB12005; Nirogacestat. DR DrugBank; DB05289; Tarenflurbil. DR MEROPS; A22.002; -. DR TCDB; 1.A.54.1.2; the presenilin er ca(2+) leak channel (presenilin) family. DR GlyGen; P49810; 1 site. DR iPTMnet; P49810; -. DR PhosphoSitePlus; P49810; -. DR SwissPalm; P49810; -. DR BioMuta; PSEN2; -. DR DMDM; 1709858; -. DR jPOST; P49810; -. DR MassIVE; P49810; -. DR PaxDb; 9606-ENSP00000355747; -. DR PeptideAtlas; P49810; -. DR ProteomicsDB; 56139; -. [P49810-1] DR ProteomicsDB; 56140; -. [P49810-2] DR ProteomicsDB; 56141; -. [P49810-3] DR Pumba; P49810; -. DR Antibodypedia; 4424; 455 antibodies from 42 providers. DR DNASU; 5664; -. DR Ensembl; ENST00000366782.6; ENSP00000355746.2; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000366783.8; ENSP00000355747.3; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000422240.6; ENSP00000403737.2; ENSG00000143801.19. [P49810-3] DR Ensembl; ENST00000524196.6; ENSP00000429036.2; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000626989.3; ENSP00000486498.2; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000677414.1; ENSP00000503116.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000678233.1; ENSP00000504728.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000679088.1; ENSP00000504727.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000679098.1; ENSP00000504303.1; ENSG00000143801.19. [P49810-1] DR GeneID; 5664; -. DR KEGG; hsa:5664; -. DR MANE-Select; ENST00000366783.8; ENSP00000355747.3; NM_000447.3; NP_000438.2. DR UCSC; uc009xeo.2; human. [P49810-1] DR AGR; HGNC:9509; -. DR ClinPGx; PA33856; -. DR CTD; 5664; -. DR DisGeNET; 5664; -. DR GeneCards; PSEN2; -. DR GeneReviews; PSEN2; -. DR HGNC; HGNC:9509; PSEN2. DR HPA; ENSG00000143801; Low tissue specificity. DR MalaCards; PSEN2; -. DR MIM; 600759; gene. DR MIM; 606889; phenotype. DR MIM; 613697; phenotype. DR OpenTargets; ENSG00000143801; -. DR Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease. DR Orphanet; 154; Familial isolated dilated cardiomyopathy. DR VEuPathDB; HostDB:ENSG00000143801; -. DR eggNOG; KOG2736; Eukaryota. DR GeneTree; ENSGT00940000157923; -. DR HOGENOM; CLU_022975_3_1_1; -. DR InParanoid; P49810; -. DR OMA; WTTITFC; -. DR OrthoDB; 20287at2759; -. DR PAN-GO; P49810; 22 GO annotations based on evolutionary models. DR PhylomeDB; P49810; -. DR PathwayCommons; P49810; -. DR Reactome; R-HSA-1251985; Nuclear signaling by ERBB4. DR Reactome; R-HSA-193692; Regulated proteolysis of p75NTR. DR Reactome; R-HSA-205043; NRIF signals cell death from the nucleus. DR Reactome; R-HSA-2122948; Activated NOTCH1 Transmits Signal to the Nucleus. DR Reactome; R-HSA-2644606; Constitutive Signaling by NOTCH1 PEST Domain Mutants. DR Reactome; R-HSA-2894862; Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants. DR Reactome; R-HSA-2979096; NOTCH2 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-3928665; EPH-ephrin mediated repulsion of cells. DR Reactome; R-HSA-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-9013700; NOTCH4 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-9017802; Noncanonical activation of NOTCH3. DR Reactome; R-HSA-9839383; TGFBR3 PTM regulation. DR SignaLink; P49810; -. DR SIGNOR; P49810; -. DR Agora; ENSG00000143801; -. DR BioGRID-ORCS; 5664; 11 hits in 1154 CRISPR screens. DR CD-CODE; 8C2F96ED; Centrosome. DR ChiTaRS; PSEN2; human. DR GeneWiki; PSEN2; -. DR GenomeRNAi; 5664; -. DR Pharos; P49810; Tchem. DR PRO; PR:P49810; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; P49810; protein. DR Bgee; ENSG00000143801; Expressed in body of pancreas and 98 other cell types or tissues. DR ExpressionAtlas; P49810; baseline and differential. DR GO; GO:0005813; C:centrosome; IDA:UniProtKB. DR GO; GO:0005769; C:early endosome; IEA:Ensembl. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HGNC-UCL. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0070765; C:gamma-secretase complex; IDA:ARUK-UCL. DR GO; GO:0005794; C:Golgi apparatus; IDA:HGNC-UCL. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0000776; C:kinetochore; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005637; C:nuclear inner membrane; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:HGNC-UCL. DR GO; GO:0042734; C:presynaptic membrane; IEA:Ensembl. DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB. DR GO; GO:0008021; C:synaptic vesicle; IEA:Ensembl. DR GO; GO:0042500; F:aspartic endopeptidase activity, intramembrane cleaving; IBA:GO_Central. DR GO; GO:0042987; P:amyloid precursor protein catabolic process; IDA:ARUK-UCL. DR GO; GO:0034205; P:amyloid-beta formation; IDA:ARUK-UCL. DR GO; GO:0055074; P:calcium ion homeostasis; IBA:GO_Central. DR GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro. DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:HGNC-UCL. DR GO; GO:1990456; P:mitochondrion-endoplasmic reticulum membrane tethering; IMP:UniProtKB. DR GO; GO:0007220; P:Notch receptor processing; TAS:HGNC-UCL. DR GO; GO:0007219; P:Notch signaling pathway; IBA:GO_Central. DR GO; GO:0016485; P:protein processing; IDA:HGNC-UCL. DR GO; GO:0110097; P:regulation of calcium import into the mitochondrion; IMP:UniProtKB. DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl. DR FunFam; 1.10.472.100:FF:000001; Presenilin; 1. DR Gene3D; 1.10.472.100; Presenilin; 1. DR InterPro; IPR001493; Pept_A22A_PS2. DR InterPro; IPR001108; Peptidase_A22A. DR InterPro; IPR006639; Preselin/SPP. DR InterPro; IPR042524; Presenilin_C. DR PANTHER; PTHR10202; PRESENILIN; 1. DR PANTHER; PTHR10202:SF24; PRESENILIN-2; 1. DR Pfam; PF01080; Presenilin; 2. DR PRINTS; PR01072; PRESENILIN. DR PRINTS; PR01074; PRESENILIN2. DR SMART; SM00730; PSN; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Alzheimer disease; Amyloidosis; KW Cardiomyopathy; Disease variant; Endoplasmic reticulum; Endosome; KW Golgi apparatus; Hydrolase; Lysosome; Membrane; Neurodegeneration; KW Notch signaling pathway; Phosphoprotein; Protease; KW Proteomics identification; Reference proteome; Transmembrane; KW Transmembrane helix. FT CHAIN 1..297 FT /note="Presenilin-2 NTF subunit" FT /evidence="ECO:0000305|PubMed:10652302, FT ECO:0000305|PubMed:15274632" FT /id="PRO_0000025603" FT CHAIN 298..448 FT /note="Presenilin-2 CTF subunit" FT /evidence="ECO:0000305|PubMed:10497236, FT ECO:0000305|PubMed:10652302, ECO:0000305|PubMed:15274632" FT /id="PRO_0000025604" FT TOPO_DOM 1..87 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 88..108 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 109..138 FT /note="Lumenal" FT /evidence="ECO:0000255" FT TRANSMEM 139..159 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 160..166 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 167..187 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 188..200 FT /note="Lumenal" FT /evidence="ECO:0000255" FT TRANSMEM 201..221 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 222..223 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 224..244 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 245..249 FT /note="Lumenal" FT /evidence="ECO:0000255" FT TRANSMEM 250..270 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 271..361 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 362..382 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 383..388 FT /note="Lumenal" FT /evidence="ECO:0000255" FT TRANSMEM 389..409 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 410..413 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT INTRAMEM 414..434 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 435..448 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 1..70 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 16..21 FT /note="Involved in late endosome/lysosome localization" FT /evidence="ECO:0000269|PubMed:27293189" FT MOTIF 414..416 FT /note="PAL" FT COMPBIAS 19..30 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 263 FT /evidence="ECO:0000305|PubMed:10652302" FT ACT_SITE 366 FT /evidence="ECO:0000305|PubMed:10497236, FT ECO:0000305|PubMed:10652302" FT MOD_RES 19 FT /note="Phosphoserine" FT /evidence="ECO:0000305|PubMed:27293189" FT MOD_RES 22 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163" FT MOD_RES 25 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163" FT MOD_RES 30 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q61144" FT VAR_SEQ 263..296 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000305" FT /id="VSP_005194" FT VAR_SEQ 324 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_043648" FT VARIANT 62 FT /note="R -> H (in AD4; likely benign; dbSNP:rs58973334)" FT /evidence="ECO:0000269|PubMed:22503161, FT ECO:0000269|PubMed:9384602" FT /id="VAR_006461" FT VARIANT 71 FT /note="R -> W (in AD4; uncertain significance; FT dbSNP:rs140501902)" FT /evidence="ECO:0000269|PubMed:21544564, FT ECO:0000269|PubMed:22503161" FT /id="VAR_070027" FT VARIANT 122 FT /note="T -> P (in AD4; does not affect localization at late FT endosome/lysosome; strongly decreased N-cadherin- and Notch FT receptor processing; ligand-dependent; does not affect FT amyloid-beta formation; dbSNP:rs63749851)" FT /evidence="ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:27293189" FT /id="VAR_009214" FT VARIANT 122 FT /note="T -> R (in AD4; increased mitochondrion-endoplasmic FT reticulum membrane tethering resulting in increased calcium FT transfer to mitochondria; dbSNP:rs28936380)" FT /evidence="ECO:0000269|PubMed:14681895, FT ECO:0000269|PubMed:21285369" FT /id="VAR_081261" FT VARIANT 126 FT /note="E -> K (in AD4; uncertain significance)" FT /evidence="ECO:0000269|PubMed:24844686" FT /id="VAR_081262" FT VARIANT 130 FT /note="S -> L (in CMD1V and AD4; uncertain significance; FT dbSNP:rs63750197)" FT /evidence="ECO:0000269|PubMed:17186461, FT ECO:0000269|PubMed:22503161" FT /id="VAR_064903" FT VARIANT 141 FT /note="N -> I (in AD4; results in altered amyloid-beta FT production and increased amyloid-beta 42/amyloid-beta 40 FT ratio; loss of function as calcium-leak channel; results in FT calcium overload in the endoplasmic reticulum; increased FT mitochondrion-endoplasmic reticulum membrane tethering FT resulting in increased calcium transfer to mitochondria; FT does not affect localization at late endosome/lysosome; FT strongly decreased N-cadherin- and Notch receptor FT processing; ligand-dependent; does not affect amyloid-beta FT formation; dbSNP:rs63750215)" FT /evidence="ECO:0000269|PubMed:16752394, FT ECO:0000269|PubMed:16959576, ECO:0000269|PubMed:21285369, FT ECO:0000269|PubMed:27293189, ECO:0000269|PubMed:7638622, FT ECO:0000269|PubMed:7651536" FT /id="VAR_006462" FT VARIANT 141 FT /note="N -> Y (in AD4; dbSNP:rs61761208)" FT /evidence="ECO:0000269|PubMed:24838186" FT /id="VAR_081263" FT VARIANT 148 FT /note="V -> I (in AD4; late-onset Alzheimer disease; FT dbSNP:rs63750812)" FT /evidence="ECO:0000269|PubMed:10732806" FT /id="VAR_007958" FT VARIANT 239 FT /note="M -> I (in AD4; Does not affect localization at late FT endosome/lysosome.Affects amyloid-beta formation.; FT dbSNP:rs63749884)" FT /evidence="ECO:0000269|PubMed:10631141, FT ECO:0000269|PubMed:27293189" FT /id="VAR_009215" FT VARIANT 239 FT /note="M -> V (in AD4; oes not affect localization at late FT endosome/lysosome; affects amyloid-beta formation; FT dbSNP:rs28936379)" FT /evidence="ECO:0000269|PubMed:27293189, FT ECO:0000269|PubMed:7651536" FT /id="VAR_006463" FT MUTAGEN 16..21 FT /note="ERTSLM->ARTSAA: Impairs AP1G1 interaction. Does not FT affect aspartic endopeptidase activity, intramembrane FT cleaving. Does not affect gamma-secretase complex assemlby. FT Significantly decreases localization at late FT endosome/lysosome." FT /evidence="ECO:0000269|PubMed:27293189" FT MUTAGEN 19 FT /note="S->A: Does not affect AP1G1 interaction. Does not FT affect aspartic endopeptidase activity, intramembrane FT cleaving. Does not affect gamma-secretase complex assemlby. FT Does not affect localization at late endosome/lysosome." FT /evidence="ECO:0000269|PubMed:27293189" FT MUTAGEN 19 FT /note="S->D: Impairs AP1G1 interaction. Does not affect FT aspartic endopeptidase activity, intramembrane cleaving. FT Does not affect gamma-secretase complex assembly. Decreases FT localization at late endosome/lysosome." FT /evidence="ECO:0000269|PubMed:27293189" FT MUTAGEN 263 FT /note="D->A: Reduces production of amyloid-beta in APP FT processing." FT /evidence="ECO:0000269|PubMed:10652302" FT MUTAGEN 366 FT /note="D->A: Reduces production of amyloid-beta in APP FT processing and of NICD in NOTCH1 processing. Increased FT mitochondrion-endoplasmic reticulum membrane tethering FT resulting in increased calcium transfer to mitochondria." FT /evidence="ECO:0000269|PubMed:10497236, FT ECO:0000269|PubMed:10652302, ECO:0000269|PubMed:21285369" FT CONFLICT 123 FT /note="P -> T (in Ref. 1; AAB59557 and 10; AAL16812)" FT /evidence="ECO:0000305" FT CONFLICT 295 FT /note="S -> L (in Ref. 10; AAL16812)" FT /evidence="ECO:0000305" FT CONFLICT 325 FT /note="Missing (in Ref. 9; AAC50290)" FT /evidence="ECO:0000305" FT CONFLICT 358..361 FT /note="RGVK -> SKGA (in Ref. 9; AAC50290)" FT /evidence="ECO:0000305" FT HELIX 86..106 FT /evidence="ECO:0007829|PDB:7Y5X" FT TURN 107..109 FT /evidence="ECO:0007829|PDB:7Y5X" FT TURN 170..173 FT /evidence="ECO:0007829|PDB:7Y5X" FT HELIX 174..180 FT /evidence="ECO:0007829|PDB:7Y5X" FT TURN 181..183 FT /evidence="ECO:0007829|PDB:7Y5X" FT HELIX 184..195 FT /evidence="ECO:0007829|PDB:7Y5X" FT HELIX 201..219 FT /evidence="ECO:0007829|PDB:7Y5X" FT HELIX 225..245 FT /evidence="ECO:0007829|PDB:7Y5X" FT TURN 249..251 FT /evidence="ECO:0007829|PDB:7Y5X" FT HELIX 252..261 FT /evidence="ECO:0007829|PDB:7Y5X" FT HELIX 364..377 FT /evidence="ECO:0007829|PDB:7Y5X" FT STRAND 380..383 FT /evidence="ECO:0007829|PDB:7Y5X" FT HELIX 385..409 FT /evidence="ECO:0007829|PDB:7Y5X" FT HELIX 416..430 FT /evidence="ECO:0007829|PDB:7Y5X" FT TURN 431..434 FT /evidence="ECO:0007829|PDB:7Y5X" FT HELIX 435..443 FT /evidence="ECO:0007829|PDB:7Y5X" SQ SEQUENCE 448 AA; 50140 MW; A927EEC623468116 CRC64; MLTFMASDSE EEVCDERTSL MSAESPTPRS CQEGRQGPED GENTAQWRSQ ENEEDGEEDP DRYVCSGVPG RPPGLEEELT LKYGAKHVIM LFVPVTLCMI VVVATIKSVR FYTEKNGQLI YTPFTEDTPS VGQRLLNSVL NTLIMISVIV VMTIFLVVLY KYRCYKFIHG WLIMSSLMLL FLFTYIYLGE VLKTYNVAMD YPTLLLTVWN FGAVGMVCIH WKGPLVLQQA YLIMISALMA LVFIKYLPEW SAWVILGAIS VYDLVAVLCP KGPLRMLVET AQERNEPIFP ALIYSSAMVW TVGMAKLDPS SQGALQLPYD PEMEEDSYDS FGEPSYPEVF EPPLTGYPGE ELEEEEERGV KLGLGDFIFY SVLVGKAAAT GSGDWNTTLA CFVAILIGLC LTLLLLAVFK KALPALPISI TFGLIFYFST DNLVRPFMDT LASHQLYI // ID TREM2_HUMAN Reviewed; 230 AA. AC Q9NZC2; Q8N5H8; Q8WYN6; DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-2000, sequence version 1. DT 28-JAN-2026, entry version 185. DE RecName: Full=Triggering receptor expressed on myeloid cells 2; DE Short=TREM-2; DE AltName: Full=Triggering receptor expressed on monocytes 2; DE Flags: Precursor; GN Name=TREM2 {ECO:0000312|HGNC:HGNC:17761}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=10799849; DOI=10.4049/jimmunol.164.10.4991; RA Bouchon A., Dietrich J., Colonna M.; RT "Inflammatory responses can be triggered by TREM-1, a novel receptor RT expressed on neutrophils and monocytes."; RL J. Immunol. 164:4991-4995(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RA Begum N.A., Tsukasa S.; RT "Identification of a novel variant of triggering receptor, TREM-2V, by mRNA RT differential display."; RL Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). 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 [4] RP FUNCTION, AND INTERACTION WITH TYROBP. RX PubMed=11602640; DOI=10.1084/jem.194.8.1111; RA Bouchon A., Hernandez-Munain C., Cella M., Colonna M.; RT "A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 RT and maturation of human dendritic cells."; RL J. Exp. Med. 194:1111-1122(2001). RN [5] RP TISSUE SPECIFICITY, INVOLVEMENT IN PLOSL2, AND VARIANTS PLOSL2 RP 44-TRP--THR-230 DEL; 78-TRP--THR-230 DEL; GLY-134 AND ASN-186. RX PubMed=12080485; DOI=10.1086/342259; RA Paloneva J., Manninen T., Christman G., Hovanes K., Mandelin J., RA Adolfsson R., Bianchin M., Bird T., Miranda R., Salmaggi A., RA Tranebjaerg L., Konttinen Y., Peltonen L.; RT "Mutations in two genes encoding different subunits of a receptor signaling RT complex result in an identical disease phenotype."; RL Am. J. Hum. Genet. 71:656-662(2002). RN [6] RP ERRATUM OF PUBMED:12080485. RA Paloneva J., Manninen T., Christman G., Hovanes K., Mandelin J., RA Adolfsson R., Bianchin M., Bird T., Miranda R., Salmaggi A., RA Tranebjaerg L., Konttinen Y., Peltonen L.; RL Am. J. Hum. Genet. 72:225-225(2003). RN [7] RP FUNCTION, INVOLVEMENT IN PLOSL2, VARIANT PLOSL2 14-GLU--THR-230 DEL, AND RP CHARACTERIZATION OF VARIANT PLOSL2 14-GLU--THR-230 DEL. RX PubMed=12925681; DOI=10.1084/jem.20030027; RA Paloneva J., Mandelin J., Kiialainen A., Bohling T., Prudlo J., Hakola P., RA Haltia M., Konttinen Y.T., Peltonen L.; RT "DAP12/TREM2 deficiency results in impaired osteoclast differentiation and RT osteoporotic features."; RL J. Exp. Med. 198:669-675(2003). RN [8] RP INVOLVEMENT IN PLOSL2, AND VARIANTS PLOSL2 33-GLN--THR-230 DEL AND GLY-126. RX PubMed=15883308; DOI=10.1212/01.wnl.0000160304.00003.ca; RA Kluenemann H.H., Ridha B.H., Magy L., Wherrett J.R., Hemelsoet D.M., RA Keen R.W., De Bleecker J.L., Rossor M.N., Marienhagen J., Klein H.E., RA Peltonen L., Paloneva J.; RT "The genetic causes of basal ganglia calcification, dementia, and bone RT cysts: DAP12 and TREM2."; RL Neurology 64:1502-1507(2005). RN [9] RP FUNCTION. RX PubMed=18957693; DOI=10.1126/scisignal.1159665; RA Helming L., Tomasello E., Kyriakides T.R., Martinez F.O., Takai T., RA Gordon S., Vivier E.; RT "Essential role of DAP12 signaling in macrophage programming into a fusion- RT competent state."; RL Sci. Signal. 1:RA11-RA11(2008). RN [10] RP INTERACTION WITH TYROBP. RX PubMed=25957402; DOI=10.1074/jbc.m115.645986; RA Zhong L., Chen X.F., Zhang Z.L., Wang Z., Shi X.Z., Xu K., Zhang Y.W., RA Xu H., Bu G.; RT "DAP12 stabilizes the C-terminal fragment of the triggering receptor RT expressed on myeloid cells-2 (TREM2) and protects against LPS-induced pro- RT inflammatory response."; RL J. Biol. Chem. 290:15866-15877(2015). RN [11] RP SUBCELLULAR LOCATION, AND PROTEOLYTIC PROCESSING. RX PubMed=24078628; DOI=10.1074/jbc.m113.517540; RA Wunderlich P., Glebov K., Kemmerling N., Tien N.T., Neumann H., Walter J.; RT "Sequential proteolytic processing of the triggering receptor expressed on RT myeloid cells-2 (TREM2) protein by ectodomain shedding and gamma-secretase- RT dependent intramembranous cleavage."; RL J. Biol. Chem. 288:33027-33036(2013). RN [12] RP FUNCTION, SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, CHARACTERIZATION OF RP VARIANTS CYS-38; HIS-47 AND MET-66, AND MUTAGENESIS OF CYS-36 AND CYS-60. RX PubMed=24990881; DOI=10.1126/scitranslmed.3009093; RA Kleinberger G., Yamanishi Y., Suarez-Calvet M., Czirr E., Lohmann E., RA Cuyvers E., Struyfs H., Pettkus N., Wenninger-Weinzierl A., Mazaheri F., RA Tahirovic S., Lleo A., Alcolea D., Fortea J., Willem M., Lammich S., RA Molinuevo J.L., Sanchez-Valle R., Antonell A., Ramirez A., Heneka M.T., RA Sleegers K., van der Zee J., Martin J.J., Engelborghs S., RA Demirtas-Tatlidede A., Zetterberg H., Van Broeckhoven C., Gurvit H., RA Wyss-Coray T., Hardy J., Colonna M., Haass C.; RT "TREM2 mutations implicated in neurodegeneration impair cell surface RT transport and phagocytosis."; RL Sci. Transl. Med. 6:243RA86-243RA86(2014). RN [13] RP SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANT AD17 HIS-47, RP CHARACTERIZATION OF VARIANTS PHE-16; MET-27; VAL-28; PHE-31; RP 33-GLN--THR-230; CYS-38; CYS-47; MET-66; ASN-87; SER-130; GLN-136; TRP-136; RP LYS-151; TYR-157; ARG-162; THR-196; GLN-215 AND ILE-223, AND VARIANT RP ASP-202 (ISOFORM 2). RX PubMed=27589997; DOI=10.1186/s40478-016-0367-7; RA Sirkis D.W., Bonham L.W., Aparicio R.E., Geier E.G., Ramos E.M., Wang Q., RA Karydas A., Miller Z.A., Miller B.L., Coppola G., Yokoyama J.S.; RT "Rare TREM2 variants associated with Alzheimer's disease display reduced RT cell surface expression."; RL Acta Neuropathol. Commun. 4:98-98(2016). RN [14] RP VARIANTS TYR-157 AND THR-192, AND VARIANTS CYS-183 AND CYS-200 (ISOFORM 2). RX PubMed=27067662; DOI=10.1016/j.neurobiolaging.2016.02.023; RA Jiang T., Tan L., Chen Q., Tan M.S., Zhou J.S., Zhu X.C., Lu H., Wang H.F., RA Zhang Y.D., Yu J.T.; RT "A rare coding variant in TREM2 increases risk for Alzheimer's disease in RT Han Chinese."; RL Neurobiol. Aging 42:E1-E3(2016). RN [15] RP FUNCTION, TISSUE SPECIFICITY, CHARACTERIZATION OF VARIANTS CYS-38; HIS-47; RP HIS-62; MET-66 AND ASN-87, AND MUTAGENESIS OF LYS-48. RX PubMed=27477018; DOI=10.1016/j.neuron.2016.06.015; RA Yeh F.L., Wang Y., Tom I., Gonzalez L.C., Sheng M.; RT "TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby RT Facilitates Uptake of Amyloid-Beta by Microglia."; RL Neuron 91:328-340(2016). RN [16] RP TISSUE SPECIFICITY, AND CHARACTERIZATION OF VARIANTS HIS-47 AND HIS-62. RX PubMed=28802038; DOI=10.1016/j.cell.2017.07.023; RA Ulland T.K., Song W.M., Huang S.C., Ulrich J.D., Sergushichev A., RA Beatty W.L., Loboda A.A., Zhou Y., Cairns N.J., Kambal A., Loginicheva E., RA Gilfillan S., Cella M., Virgin H.W., Unanue E.R., Wang Y., Artyomov M.N., RA Holtzman D.M., Colonna M.; RT "TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease."; RL Cell 170:649-663(2017). RN [17] RP SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, AND CHARACTERIZATION OF RP VARIANT TYR-157. RX PubMed=28855300; DOI=10.15252/emmm.201707672; RA Schlepckow K., Kleinberger G., Fukumori A., Feederle R., RA Lichtenthaler S.F., Steiner H., Haass C.; RT "An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and RT affects shedding and phagocytic function."; RL EMBO Mol. Med. 9:1356-1365(2017). RN [18] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, PROTEOLYTIC PROCESSING, AND RP CHARACTERIZATION OF VARIANT TYR-157. RX PubMed=28855301; DOI=10.15252/emmm.201707673; RA Thornton P., Sevalle J., Deery M.J., Fraser G., Zhou Y., Staahl S., RA Franssen E.H., Dodd R.B., Qamar S., Gomez Perez-Nievas B., Nicol L.S., RA Eketjaell S., Revell J., Jones C., Billinton A., St George-Hyslop P.H., RA Chessell I., Crowther D.C.; RT "TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the RT Alzheimer's disease-associated H157Y variant."; RL EMBO Mol. Med. 9:1366-1378(2017). RN [19] RP SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANTS CYS-38 AND MET-66, AND RP CHARACTERIZATION OF VARIANTS PLOSL2 GLY-126; GLY-134 AND ASN-186. RX PubMed=28768830; DOI=10.1091/mbc.e17-06-0423; RA Sirkis D.W., Aparicio R.E., Schekman R.; RT "Neurodegeneration-associated mutant TREM2 proteins abortively cycle RT between the ER and ER-Golgi intermediate compartment."; RL Mol. Biol. Cell 28:2723-2733(2017). RN [20] RP SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, AND CHARACTERIZATION OF RP VARIANT HIS-47. RX PubMed=28923481; DOI=10.1016/j.neulet.2017.09.034; RA Feuerbach D., Schindler P., Barske C., Joller S., Beng-Louka E., RA Worringer K.A., Kommineni S., Kaykas A., Ho D.J., Ye C., Welzenbach K., RA Elain G., Klein L., Brzak I., Mir A.K., Farady C.J., Aichholz R., Popp S., RA George N., Neumann U.; RT "ADAM17 is the main sheddase for the generation of human triggering RT receptor expressed in myeloid cells (hTREM2) ectodomain and cleaves TREM2 RT after Histidine 157."; RL Neurosci. Lett. 660:109-114(2017). RN [21] RP CHARACTERIZATION OF VARIANT HIS-47. RX PubMed=30442540; DOI=10.1016/j.jalz.2018.09.006; RA Claes C., Van Den Daele J., Boon R., Schouteden S., Colombo A., RA Monasor L.S., Fiers M., Ordovas L., Nami F., Bohrmann B., Tahirovic S., RA De Strooper B., Verfaillie C.M.; RT "Human stem cell-derived monocytes and microglia-like cells reveal impaired RT amyloid plaque clearance upon heterozygous or homozygous loss of TREM2."; RL Alzheimers Dement. 15:453-464(2018). RN [22] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=29752066; DOI=10.1016/j.immuni.2018.04.016; RA Filipello F., Morini R., Corradini I., Zerbi V., Canzi A., Michalski B., RA Erreni M., Markicevic M., Starvaggi-Cucuzza C., Otero K., Piccio L., RA Cignarella F., Perrucci F., Tamborini M., Genua M., Rajendran L., Menna E., RA Vetrano S., Fahnestock M., Paolicelli R.C., Matteoli M.; RT "The Microglial Innate Immune Receptor TREM2 Is Required for Synapse RT Elimination and Normal Brain Connectivity."; RL Immunity 48:979-991(2018). RN [23] RP FUNCTION, AND CHARACTERIZATION OF VARIANTS HIS-47 AND HIS-62. RX PubMed=29518356; DOI=10.1016/j.neuron.2018.01.031; RA Zhao Y., Wu X., Li X., Jiang L.L., Gui X., Liu Y., Sun Y., Zhu B., RA Pina-Crespo J.C., Zhang M., Zhang N., Chen X., Bu G., An Z., Huang T.Y., RA Xu H.; RT "TREM2 Is a Receptor for beta-Amyloid that Mediates Microglial Function."; RL Neuron 97:1023-1031(2018). RN [24] {ECO:0007744|PDB:5ELI} RP X-RAY CRYSTALLOGRAPHY (3.10 ANGSTROMS) OF 19-133, DISULFIDE BONDS, SUBUNIT, RP SUBCELLULAR LOCATION, MUTAGENESIS OF ASN-68; ARG-76 AND ARG-77, RP GLYCOSYLATION AT ASN-79, CHARACTERIZATION OF VARIANTS CYS-38; HIS-47; RP HIS-62; MET-66; ASN-87 AND LYS-96, AND CHARACTERIZATION OF VARIANT PLOSL2 RP GLY-126. RX PubMed=27995897; DOI=10.7554/elife.20391; RA Kober D.L., Alexander-Brett J.M., Karch C.M., Cruchaga C., Colonna M., RA Holtzman M.J., Brett T.J.; RT "Neurodegenerative disease mutations in TREM2 reveal a functional surface RT and distinct loss-of-function mechanisms."; RL Elife 5:E20391-E20391(2016). RN [25] {ECO:0007744|PDB:6B8O} RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 19-174 IN COMPLEX WITH RP PHOSPHATIDYLSERINE, PHOSPHOLIPID-BINDING, DISULFIDE BONDS, FUNCTION, RP SUBUNIT, GLYCOSYLATION AT ASN-20 AND ASN-79, CHARACTERIZATION OF VARIANT RP HIS-47, AND MUTAGENESIS OF ASN-20. RX PubMed=29794134; DOI=10.1074/jbc.ra118.002352; RA Sudom A., Talreja S., Danao J., Bragg E., Kegel R., Min X., Richardson J., RA Zhang Z., Sharkov N., Marcora E., Thibault S., Bradley J., Wood S., RA Lim A.C., Chen H., Wang S., Foltz I.N., Sambashivan S., Wang Z.; RT "Molecular basis for the loss-of-function effects of the Alzheimer's RT disease-associated R47H variant of the immune receptor TREM2."; RL J. Biol. Chem. 293:12634-12646(2018). RN [26] RP INVOLVEMENT IN PLOSL2, AND VARIANT PLOSL2 33-GLN--THR-230 DEL. RX PubMed=12754369; DOI=10.1136/jnnp.74.6.825-a; RA Soragna D., Papi L., Ratti M.T., Sestini R., Tupler R., Montalbetti L.; RT "An Italian family affected by Nasu-Hakola disease with a novel genetic RT mutation in the TREM2 gene."; RL J. Neurol. Neurosurg. Psych. 74:825-826(2003). RN [27] RP INVOLVEMENT IN PLOSL2, AND VARIANT PLOSL2 33-GLN--THR-230 DEL. RX PubMed=23399524; DOI=10.1016/j.jns.2013.01.021; RA Bock V., Botturi A., Gaviani P., Lamperti E., Maccagnano C., Piccio L., RA Silvani A., Salmaggi A.; RT "Polycystic Lipomembranous Osteodysplasia with Sclerosing RT Leukoencephalopathy (PLOSL): a new report of an Italian woman and review of RT the literature."; RL J. Neurol. Sci. 326:115-119(2013). RN [28] RP CHARACTERIZATION OF VARIANT PLOSL2 33-GLN--THR-230 DEL, CHARACTERIZATION OF RP VARIANTS CYS-38; HIS-47 AND MET-66, AND SUBCELLULAR LOCATION. RX PubMed=25615530; DOI=10.1111/tra.12264; RA Park J.S., Ji I.J., An H.J., Kang M.J., Kang S.W., Kim D.H., Yoon S.Y.; RT "Disease-associated mutations of TREM2 alter the processing of N-linked RT oligosaccharides in the Golgi apparatus."; RL Traffic 16:510-518(2015). RN [29] RP VARIANT PLOSL2 33-GLN--THR-230 DEL. RX PubMed=29142083; DOI=10.1212/wnl.0000000000004747; RA Ghezzi L., Carandini T., Arighi A., Fenoglio C., Arcaro M., De Riz M., RA Pietroboni A.M., Fumagalli G.G., Basilico P., Calvi A., Scarioni M., RA Colombi A., Serpente M., Marotta G., Benti R., Scarpini E., Galimberti D.; RT "Evidence of CNS beta-amyloid deposition in Nasu-Hakola disease due to the RT TREM2 Q33X mutation."; RL Neurology 89:2503-2505(2017). RN [30] RP INVOLVEMENT IN AD17, AND VARIANT AD17 HIS-47. RX PubMed=23150908; DOI=10.1056/nejmoa1211103; RA Jonsson T., Stefansson H., Steinberg S., Jonsdottir I., Jonsson P.V., RA Snaedal J., Bjornsson S., Huttenlocher J., Levey A.I., Lah J.J., RA Rujescu D., Hampel H., Giegling I., Andreassen O.A., Engedal K., RA Ulstein I., Djurovic S., Ibrahim-Verbaas C., Hofman A., Ikram M.A., RA van Duijn C.M., Thorsteinsdottir U., Kong A., Stefansson K.; RT "Variant of TREM2 associated with the risk of Alzheimer's disease."; RL N. Engl. J. Med. 368:107-116(2013). RN [31] RP INVOLVEMENT IN AD17, VARIANTS AD17 HIS-47 AND HIS-62, VARIANTS RP 33-GLN--THR-230 DEL; HIS-52; MET-66; ASN-87; LYS-96; TRP-136; GLN-136; RP LYS-151; TYR-157; PRO-211; GLN-215 AND ILE-223, AND VARIANTS RP 191-TRP--THR-230 DEL AND ASP-202 (ISOFORM 2). RX PubMed=24899047; DOI=10.1093/hmg/ddu277; RA Jin S.C., Benitez B.A., Karch C.M., Cooper B., Skorupa T., Carrell D., RA Norton J.B., Hsu S., Harari O., Cai Y., Bertelsen S., Goate A.M., RA Cruchaga C.; RT "Coding variants in TREM2 increase risk for Alzheimer's disease."; RL Hum. Mol. Genet. 23:5838-5846(2014). RN [32] RP INVOLVEMENT IN AD17, AND VARIANTS AD17 HIS-47 AND HIS-62. RX PubMed=38899702; DOI=10.1056/nejmc2314334; RA Stefansson H., Walters G.B., Sveinbjornsson G., Tragante V., Einarsson G., RA Helgason H., Sigurdsson A., Beyter D., Snaebjarnarson A.S., RA Ivarsdottir E.V., Thorleifsson G., Halldorsson B.V., Norddahl G., RA Styrkarsdottir U., Sturluson A., Holm H., Helgason A., Moore K., RA Eggertsson H.P., Oddsson A.H., Jonsdottir G.A., Gunnarsson A.F., RA Bjornsdottir G., Gisladottir R.S., Thorgeirsson T.E., Skuladottir A., RA Gudbjartsson D.F., Sulem P., Jonsson P., Thordardottir S., Snaedal J., RA Eyjolfsdottir H., Creese B., Ballard C., Corbett A., RA Vasconcelos Da Silva M., Aarsland D., Andreassen O.A., Selbaek G., RA Djurovic S., Stordal E., Fladby T., Haavik J., Igland J., Giil L.M., RA Eriksson S., Hallmans G., Loevheim H., Lopatko Lindman K., Trupp M., RA Forsgren L., Werge T., Banasik K., Brunak S., Ullum H., Frikke-Schmidt R., RA Ostrowski S.R., Didriksen M., Soerensen E., Simonsen A.H., Nielsen J.E., RA Waldemar G., Pedersen O.B., Erikstrup C., Knowlton K.U., Nadauld L.D., RA Stefansson K.; RT "Homozygosity for R47H in TREM2 and the Risk of Alzheimer's Disease."; RL N. Engl. J. Med. 390:2217-2219(2024). CC -!- FUNCTION: Forms a receptor signaling complex with TYROBP which mediates CC signaling and cell activation following ligand binding CC (PubMed:10799849). Acts as a receptor for amyloid-beta protein 42, a CC cleavage product of the amyloid-beta precursor protein APP, and CC mediates its uptake and degradation by microglia (PubMed:27477018, CC PubMed:29518356). Binding to amyloid-beta 42 mediates microglial CC activation, proliferation, migration, apoptosis and expression of pro- CC inflammatory cytokines, such as IL6R and CCL3, and the anti- CC inflammatory cytokine ARG1 (By similarity). Acts as a receptor for CC lipoprotein particles such as LDL, VLDL, and HDL and for CC apolipoproteins such as APOA1, APOA2, APOB, APOE, APOE2, APOE3, APOE4, CC and CLU and enhances their uptake in microglia (PubMed:27477018). Binds CC phospholipids (preferably anionic lipids) such as phosphatidylserine, CC phosphatidylethanolamine, phosphatidylglycerol and sphingomyelin CC (PubMed:29794134). Regulates microglial proliferation by acting as an CC upstream regulator of the Wnt/beta-catenin signaling cascade (By CC similarity). Required for microglial phagocytosis of apoptotic neurons CC (PubMed:24990881). Also required for microglial activation and CC phagocytosis of myelin debris after neuronal injury and of neuronal CC synapses during synapse elimination in the developing brain (By CC similarity). Regulates microglial chemotaxis and process outgrowth, and CC also the microglial response to oxidative stress and lipopolysaccharide CC (By similarity). It suppresses PI3K and NF-kappa-B signaling in CC response to lipopolysaccharide; thus promoting phagocytosis, CC suppressing pro-inflammatory cytokine and nitric oxide production, CC inhibiting apoptosis and increasing expression of IL10 and TGFB (By CC similarity). During oxidative stress, it promotes anti-apoptotic NF- CC kappa-B signaling and ERK signaling (By similarity). Plays a role in CC microglial MTOR activation and metabolism (By similarity). Regulates CC age-related changes in microglial numbers (PubMed:29752066). Triggers CC activation of the immune responses in macrophages and dendritic cells CC (PubMed:10799849). Mediates cytokine-induced formation of CC multinucleated giant cells which are formed by the fusion of CC macrophages (By similarity). In dendritic cells, receptor of SEMA6D CC with PLEXNA1 as coreceptor and mediates up-regulation of chemokine CC receptor CCR7 and dendritic cell maturation and survival CC (PubMed:11602640). Involved in the positive regulation of osteoclast CC differentiation (PubMed:12925681). {ECO:0000250|UniProtKB:Q99NH8, CC ECO:0000269|PubMed:10799849, ECO:0000269|PubMed:11602640, CC ECO:0000269|PubMed:12925681, ECO:0000269|PubMed:24990881, CC ECO:0000269|PubMed:27477018, ECO:0000269|PubMed:29518356, CC ECO:0000269|PubMed:29752066, ECO:0000269|PubMed:29794134}. CC -!- SUBUNIT: Monomer (PubMed:27995897). After ectodomain shedding, the CC extracellular domain oligomerizes, which is enhanced and stabilized by CC binding of phosphatidylserine (PubMed:29794134). Interacts with CC TYROBP/DAP12 (PubMed:11602640, PubMed:25957402). Interaction with CC TYROBP is required for stabilization of the TREM2 C-terminal fragment CC (TREM2-CTF) which is produced by proteolytic processing CC (PubMed:25957402). Interacts with PLXNA1 (via TIG domains); the CC interaction mediates SEMA6D binding and signaling through TYROBP (By CC similarity). {ECO:0000250|UniProtKB:Q99NH8, CC ECO:0000269|PubMed:11602640, ECO:0000269|PubMed:25957402, CC ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:29794134}. CC -!- INTERACTION: CC Q9NZC2; P02649: APOE; NbExp=4; IntAct=EBI-14036387, EBI-1222467; CC Q9NZC2; PRO_0000000092 [P05067]: APP; NbExp=4; IntAct=EBI-14036387, EBI-821758; CC Q9NZC2; P49768: PSEN1; NbExp=5; IntAct=EBI-14036387, EBI-297277; CC Q9NZC2; O43914: TYROBP; NbExp=4; IntAct=EBI-14036387, EBI-2214794; CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane CC {ECO:0000269|PubMed:24078628, ECO:0000269|PubMed:24990881, CC ECO:0000269|PubMed:25615530, ECO:0000269|PubMed:27589997, CC ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:28768830, CC ECO:0000269|PubMed:28855300, ECO:0000269|PubMed:28855301, CC ECO:0000269|PubMed:28923481}; Single-pass type I membrane protein CC {ECO:0000255}. CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Secreted {ECO:0000305}. CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Secreted {ECO:0000305}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q9NZC2-1; Sequence=Displayed; CC Name=2; Synonyms=TREM-2V; CC IsoId=Q9NZC2-2; Sequence=VSP_010792; CC Name=3; CC IsoId=Q9NZC2-3; Sequence=VSP_010793; CC -!- TISSUE SPECIFICITY: Expressed in the brain, specifically in microglia CC and in the fusiform gyrus (at protein level) (PubMed:27477018, CC PubMed:28802038, PubMed:28855300, PubMed:29752066). Expressed on CC macrophages and dendritic cells but not on granulocytes or monocytes CC (PubMed:10799849, PubMed:28855301). In the CNS strongest expression CC seen in the basal ganglia, corpus callosum, medulla oblongata and CC spinal cord (PubMed:12080485). {ECO:0000269|PubMed:10799849, CC ECO:0000269|PubMed:12080485, ECO:0000269|PubMed:27477018, CC ECO:0000269|PubMed:28802038, ECO:0000269|PubMed:28855300, CC ECO:0000269|PubMed:28855301, ECO:0000269|PubMed:29752066}. CC -!- PTM: Undergoes ectodomain shedding through proteolytic cleavage by CC ADAM10 and ADAM17 to produce a transmembrane segment, the TREM2 C- CC terminal fragment (TREM2-CTF), which is subsequently cleaved by gamma- CC secretase. {ECO:0000269|PubMed:24078628, ECO:0000269|PubMed:24990881, CC ECO:0000269|PubMed:28855300, ECO:0000269|PubMed:28855301, CC ECO:0000269|PubMed:28923481}. CC -!- DISEASE: Polycystic lipomembranous osteodysplasia with sclerosing CC leukoencephalopathy 2 (PLOSL2) [MIM:618193]: An autosomal recessive CC disease characterized by presenile frontal dementia with CC leukoencephalopathy and basal ganglia calcification. In most cases the CC disorder first manifests in early adulthood as pain and swelling in CC ankles and feet, followed by bone fractures. Neurologic symptoms CC manifest in the fourth decade of life as a frontal lobe syndrome with CC loss of judgment, euphoria, and disinhibition. Progressive decline in CC other cognitive domains begins to develop at about the same time. The CC disorder culminates in a profound dementia and death by age 50 years. CC {ECO:0000269|PubMed:12080485, ECO:0000269|PubMed:12754369, CC ECO:0000269|PubMed:12925681, ECO:0000269|PubMed:15883308, CC ECO:0000269|PubMed:23399524, ECO:0000269|PubMed:25615530, CC ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:28768830, CC ECO:0000269|PubMed:28923481, ECO:0000269|PubMed:29142083}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Alzheimer disease 17 (AD17) [MIM:615080]: A late-onset form of CC Alzheimer disease. Alzheimer disease is a neurodegenerative disorder CC characterized by progressive dementia, loss of cognitive abilities, and CC deposition of fibrillar amyloid proteins as intraneuronal CC neurofibrillary tangles, extracellular amyloid plaques and vascular CC amyloid deposits. The major constituents of these plaques are CC neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that CC are produced by the proteolysis of the transmembrane APP protein. The CC cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, CC such as C31, are also implicated in neuronal death. CC {ECO:0000269|PubMed:23150908, ECO:0000269|PubMed:24899047, CC ECO:0000269|PubMed:27589997, ECO:0000269|PubMed:38899702}. Note=Disease CC susceptibility is associated with variants affecting the gene CC represented in this entry. CC -!- SEQUENCE CAUTION: CC Sequence=BAB78736.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={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; AF213457; AAF69824.1; -; mRNA. DR EMBL; AB062787; BAB78736.1; ALT_INIT; mRNA. DR EMBL; BC032362; AAH32362.1; -; mRNA. DR CCDS; CCDS4852.1; -. [Q9NZC2-1] DR CCDS; CCDS64422.1; -. [Q9NZC2-2] DR RefSeq; NP_001258750.1; NM_001271821.2. [Q9NZC2-2] DR RefSeq; NP_061838.1; NM_018965.4. [Q9NZC2-1] DR PDB; 5ELI; X-ray; 3.10 A; A/B=19-133. DR PDB; 5UD7; X-ray; 2.20 A; A/B/C/D/E/F=19-174. DR PDB; 5UD8; X-ray; 1.80 A; A/B=19-130. DR PDB; 6B8O; X-ray; 2.20 A; A/B/C/D/E/F=19-174. DR PDB; 6XDS; X-ray; 1.47 A; A=18-135. DR PDB; 6Y6C; X-ray; 2.26 A; A/B=19-174. DR PDB; 6YMQ; X-ray; 3.07 A; D000/G/H/I/J/K=19-131. DR PDB; 6YYE; X-ray; 3.36 A; A/B=19-131. DR PDB; 6Z0G; NMR; -; A=161-206. DR PDB; 6Z0H; NMR; -; A=161-206. DR PDB; 6Z0I; NMR; -; A=161-206. DR PDB; 8T51; X-ray; 1.90 A; E/F=148-166. DR PDB; 8T59; X-ray; 2.00 A; E/F=148-166. DR PDB; 9PWN; X-ray; 1.80 A; A=131-148. DR PDB; 9PX5; X-ray; 3.70 A; A=18-135. DR PDBsum; 5ELI; -. DR PDBsum; 5UD7; -. DR PDBsum; 5UD8; -. DR PDBsum; 6B8O; -. DR PDBsum; 6XDS; -. DR PDBsum; 6Y6C; -. DR PDBsum; 6YMQ; -. DR PDBsum; 6YYE; -. DR PDBsum; 6Z0G; -. DR PDBsum; 6Z0H; -. DR PDBsum; 6Z0I; -. DR PDBsum; 8T51; -. DR PDBsum; 8T59; -. DR PDBsum; 9PWN; -. DR PDBsum; 9PX5; -. DR AlphaFoldDB; Q9NZC2; -. DR SMR; Q9NZC2; -. DR BioGRID; 119925; 25. DR FunCoup; Q9NZC2; 306. DR IntAct; Q9NZC2; 9. DR STRING; 9606.ENSP00000362205; -. DR TCDB; 8.A.218.1.1; the triggering receptor expressed on myeloid cells 2 (trem2) family. DR GlyCosmos; Q9NZC2; 2 sites, No reported glycans. DR GlyGen; Q9NZC2; 2 sites. DR iPTMnet; Q9NZC2; -. DR PhosphoSitePlus; Q9NZC2; -. DR BioMuta; TREM2; -. DR DMDM; 50401689; -. DR MassIVE; Q9NZC2; -. DR PaxDb; 9606-ENSP00000362205; -. DR PeptideAtlas; Q9NZC2; -. DR ProteomicsDB; 83358; -. [Q9NZC2-1] DR ProteomicsDB; 83359; -. [Q9NZC2-2] DR ProteomicsDB; 83360; -. [Q9NZC2-3] DR ABCD; Q9NZC2; 4 sequenced antibodies. DR Antibodypedia; 2280; 739 antibodies from 39 providers. DR DNASU; 54209; -. DR Ensembl; ENST00000338469.3; ENSP00000342651.4; ENSG00000095970.18. [Q9NZC2-2] DR Ensembl; ENST00000373113.8; ENSP00000362205.3; ENSG00000095970.18. [Q9NZC2-1] DR Ensembl; ENST00000373122.8; ENSP00000362214.4; ENSG00000095970.18. [Q9NZC2-3] DR GeneID; 54209; -. DR KEGG; hsa:54209; -. DR MANE-Select; ENST00000373113.8; ENSP00000362205.3; NM_018965.4; NP_061838.1. DR UCSC; uc003opy.4; human. [Q9NZC2-1] DR AGR; HGNC:17761; -. DR ClinPGx; PA38468; -. DR CTD; 54209; -. DR DisGeNET; 54209; -. DR GeneCards; TREM2; -. DR GeneReviews; TREM2; -. DR HGNC; HGNC:17761; TREM2. DR HPA; ENSG00000095970; Tissue enhanced (brain, choroid plexus). DR MalaCards; TREM2; -. DR MIM; 605086; gene. DR MIM; 615080; phenotype. DR MIM; 618193; phenotype. DR NIAGADS; ENSG00000095970; -. DR OpenTargets; ENSG00000095970; -. DR Orphanet; 803; Amyotrophic lateral sclerosis. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease. DR Orphanet; 2770; Nasu-Hakola disease. DR Orphanet; 100070; Progressive non-fluent aphasia. DR Orphanet; 100069; Semantic dementia. DR VEuPathDB; HostDB:ENSG00000095970; -. DR eggNOG; ENOG502S4HV; Eukaryota. DR GeneTree; ENSGT00470000042297; -. DR HOGENOM; CLU_076120_0_0_1; -. DR InParanoid; Q9NZC2; -. DR OMA; CAPSFRH; -. DR OrthoDB; 9805957at2759; -. DR PAN-GO; Q9NZC2; 8 GO annotations based on evolutionary models. DR PhylomeDB; Q9NZC2; -. DR PathwayCommons; Q9NZC2; -. DR Reactome; R-HSA-198933; Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell. DR Reactome; R-HSA-2172127; DAP12 interactions. DR Reactome; R-HSA-2424491; DAP12 signaling. DR Reactome; R-HSA-416700; Other semaphorin interactions. DR SignaLink; Q9NZC2; -. DR Agora; ENSG00000095970; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 54209; 13 hits in 1137 CRISPR screens. DR ChiTaRS; TREM2; human. DR GeneWiki; TREM2; -. DR GenomeRNAi; 54209; -. DR Pharos; Q9NZC2; Tbio. DR PRO; PR:Q9NZC2; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; Q9NZC2; protein. DR Bgee; ENSG00000095970; Expressed in C1 segment of cervical spinal cord and 133 other cell types or tissues. DR ExpressionAtlas; Q9NZC2; baseline and differential. DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell. DR GO; GO:0016020; C:membrane; IDA:BHF-UCL. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0044853; C:plasma membrane raft; IDA:ARUK-UCL. DR GO; GO:0002116; C:semaphorin receptor complex; ISS:UniProt. DR GO; GO:0001540; F:amyloid-beta binding; IPI:ARUK-UCL. DR GO; GO:0034186; F:apolipoprotein A-I binding; IPI:ARUK-UCL. DR GO; GO:0034185; F:apolipoprotein binding; IPI:ARUK-UCL. DR GO; GO:0008013; F:beta-catenin binding; IPI:ARUK-UCL. DR GO; GO:0008035; F:high-density lipoprotein particle binding; IDA:ARUK-UCL. DR GO; GO:0019209; F:kinase activator activity; IMP:ARUK-UCL. DR GO; GO:0008289; F:lipid binding; TAS:ARUK-UCL. DR GO; GO:0001530; F:lipopolysaccharide binding; IEA:Ensembl. DR GO; GO:0071813; F:lipoprotein particle binding; IDA:ARUK-UCL. DR GO; GO:0070891; F:lipoteichoic acid binding; IEA:Ensembl. DR GO; GO:0030169; F:low-density lipoprotein particle binding; IDA:ARUK-UCL. DR GO; GO:0042834; F:peptidoglycan binding; IEA:Ensembl. DR GO; GO:0008429; F:phosphatidylethanolamine binding; IDA:ARUK-UCL. DR GO; GO:0001786; F:phosphatidylserine binding; IDA:ARUK-UCL. DR GO; GO:0005543; F:phospholipid binding; IDA:UniProtKB. DR GO; GO:1990782; F:protein tyrosine kinase binding; ISS:ARUK-UCL. DR GO; GO:0044877; F:protein-containing complex binding; IPI:ARUK-UCL. DR GO; GO:0097110; F:scaffold protein binding; IPI:BHF-UCL. DR GO; GO:0017154; F:semaphorin receptor activity; IEA:Ensembl. DR GO; GO:0030215; F:semaphorin receptor binding; IEA:Ensembl. DR GO; GO:0038023; F:signaling receptor activity; IMP:ARUK-UCL. DR GO; GO:0120146; F:sulfatide binding; IDA:ARUK-UCL. DR GO; GO:0004888; F:transmembrane signaling receptor activity; IDA:UniProt. DR GO; GO:0034189; F:very-low-density lipoprotein particle binding; IDA:ARUK-UCL. DR GO; GO:0097242; P:amyloid-beta clearance; IDA:UniProt. DR GO; GO:0150094; P:amyloid-beta clearance by cellular catabolic process; IMP:ARUK-UCL. DR GO; GO:0043277; P:apoptotic cell clearance; ISS:UniProtKB. DR GO; GO:0048143; P:astrocyte activation; ISS:ARUK-UCL. DR GO; GO:1904646; P:cellular response to amyloid-beta; IDA:UniProt. DR GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl. DR GO; GO:0071396; P:cellular response to lipid; IMP:ARUK-UCL. DR GO; GO:0071402; P:cellular response to lipoprotein particle stimulus; IDA:UniProt. DR GO; GO:0071223; P:cellular response to lipoteichoic acid; IEA:Ensembl. DR GO; GO:0140052; P:cellular response to oxidised low-density lipoprotein particle stimulus; IDA:ARUK-UCL. DR GO; GO:0071224; P:cellular response to peptidoglycan; IEA:Ensembl. DR GO; GO:0150062; P:complement-mediated synapse pruning; ISS:ARUK-UCL. DR GO; GO:0038160; P:CXCL12-activated CXCR4 signaling pathway; IMP:ARUK-UCL. DR GO; GO:0050829; P:defense response to Gram-negative bacterium; ISS:ARUK-UCL. DR GO; GO:0097028; P:dendritic cell differentiation; IDA:BHF-UCL. DR GO; GO:0097062; P:dendritic spine maintenance; ISS:ARUK-UCL. DR GO; GO:0032497; P:detection of lipopolysaccharide; IEA:Ensembl. DR GO; GO:0070392; P:detection of lipoteichoic acid; IEA:Ensembl. DR GO; GO:0032499; P:detection of peptidoglycan; IEA:Ensembl. DR GO; GO:1905805; P:excitatory synapse pruning; ISS:ARUK-UCL. DR GO; GO:0006959; P:humoral immune response; TAS:ProtInc. DR GO; GO:0098657; P:import into cell; ISS:ARUK-UCL. DR GO; GO:0055088; P:lipid homeostasis; ISS:ARUK-UCL. DR GO; GO:0007613; P:memory; IDA:ARUK-UCL. DR GO; GO:0001774; P:microglial cell activation; ISS:ARUK-UCL. DR GO; GO:0002282; P:microglial cell activation involved in immune response; ISS:ARUK-UCL. DR GO; GO:0061518; P:microglial cell proliferation; ISS:ARUK-UCL. DR GO; GO:1905907; P:negative regulation of amyloid fibril formation; ISS:ARUK-UCL. DR GO; GO:0061889; P:negative regulation of astrocyte activation; ISS:ARUK-UCL. DR GO; GO:1904093; P:negative regulation of autophagic cell death; ISS:ARUK-UCL. DR GO; GO:0010507; P:negative regulation of autophagy; ISS:ARUK-UCL. DR GO; GO:0043124; P:negative regulation of canonical NF-kappaB signal transduction; ISS:ARUK-UCL. DR GO; GO:0050866; P:negative regulation of cell activation; ISS:ARUK-UCL. DR GO; GO:0010887; P:negative regulation of cholesterol storage; ISS:ARUK-UCL. DR GO; GO:1900016; P:negative regulation of cytokine production involved in inflammatory response; ISS:ARUK-UCL. DR GO; GO:0070345; P:negative regulation of fat cell proliferation; ISS:ARUK-UCL. DR GO; GO:0034351; P:negative regulation of glial cell apoptotic process; ISS:ARUK-UCL. DR GO; GO:0002862; P:negative regulation of inflammatory response to antigenic stimulus; ISS:ARUK-UCL. DR GO; GO:0032691; P:negative regulation of interleukin-1 beta production; IEA:Ensembl. DR GO; GO:1902227; P:negative regulation of macrophage colony-stimulating factor signaling pathway; IMP:ARUK-UCL. DR GO; GO:0150079; P:negative regulation of neuroinflammatory response; IMP:ARUK-UCL. DR GO; GO:1900226; P:negative regulation of NLRP3 inflammasome complex assembly; IMP:ARUK-UCL. DR GO; GO:1903753; P:negative regulation of p38MAPK cascade; ISS:ARUK-UCL. DR GO; GO:0051898; P:negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IMP:ARUK-UCL. DR GO; GO:0034136; P:negative regulation of toll-like receptor 2 signaling pathway; ISS:ARUK-UCL. DR GO; GO:0034144; P:negative regulation of toll-like receptor 4 signaling pathway; ISS:ARUK-UCL. DR GO; GO:0010891; P:negative regulation of triglyceride storage; ISS:ARUK-UCL. DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; IEA:Ensembl. DR GO; GO:0030316; P:osteoclast differentiation; IMP:UniProtKB. DR GO; GO:0006911; P:phagocytosis, engulfment; IEA:Ensembl. DR GO; GO:0006910; P:phagocytosis, recognition; IMP:ARUK-UCL. DR GO; GO:1900223; P:positive regulation of amyloid-beta clearance; IMP:ARUK-UCL. DR GO; GO:0002588; P:positive regulation of antigen processing and presentation of peptide antigen via MHC class II; IDA:BHF-UCL. DR GO; GO:2001171; P:positive regulation of ATP biosynthetic process; ISS:ARUK-UCL. DR GO; GO:1903082; P:positive regulation of C-C chemokine receptor CCR7 signaling pathway; IDA:BHF-UCL. DR GO; GO:0050850; P:positive regulation of calcium-mediated signaling; IDA:BHF-UCL. DR GO; GO:1905291; P:positive regulation of CAMKK-AMPK signaling cascade; ISS:ARUK-UCL. DR GO; GO:2000350; P:positive regulation of CD40 signaling pathway; IDA:BHF-UCL. DR GO; GO:0050921; P:positive regulation of chemotaxis; ISS:ARUK-UCL. DR GO; GO:0010875; P:positive regulation of cholesterol efflux; ISS:ARUK-UCL. DR GO; GO:0045960; P:positive regulation of complement activation, classical pathway; ISS:ARUK-UCL. DR GO; GO:1901076; P:positive regulation of engulfment of apoptotic cell; IMP:UniProtKB. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:BHF-UCL. DR GO; GO:1904951; P:positive regulation of establishment of protein localization; ISS:ARUK-UCL. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:ARUK-UCL. DR GO; GO:0010983; P:positive regulation of high-density lipoprotein particle clearance; ISS:ARUK-UCL. DR GO; GO:0032733; P:positive regulation of interleukin-10 production; IEA:Ensembl. DR GO; GO:1902533; P:positive regulation of intracellular signal transduction; IDA:ARUK-UCL. DR GO; GO:1905581; P:positive regulation of low-density lipoprotein particle clearance; ISS:ARUK-UCL. DR GO; GO:0034241; P:positive regulation of macrophage fusion; ISS:UniProtKB. DR GO; GO:1903980; P:positive regulation of microglial cell activation; IMP:UniProtKB. DR GO; GO:1904141; P:positive regulation of microglial cell migration; IMP:ARUK-UCL. DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IEA:Ensembl. DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; IEA:Ensembl. DR GO; GO:0050766; P:positive regulation of phagocytosis; IMP:ARUK-UCL. DR GO; GO:0060100; P:positive regulation of phagocytosis, engulfment; IMP:UniProtKB. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; ISS:ARUK-UCL. DR GO; GO:0043268; P:positive regulation of potassium ion transport; ISS:ARUK-UCL. DR GO; GO:1901800; P:positive regulation of proteasomal protein catabolic process; ISS:ARUK-UCL. DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; IDA:BHF-UCL. DR GO; GO:0050714; P:positive regulation of protein secretion; IMP:UniProtKB. DR GO; GO:1905808; P:positive regulation of synapse pruning; IMP:ARUK-UCL. DR GO; GO:0032008; P:positive regulation of TOR signaling; ISS:ARUK-UCL. DR GO; GO:0070269; P:pyroptotic inflammatory response; ISS:ARUK-UCL. DR GO; GO:1900015; P:regulation of cytokine production involved in inflammatory response; ISS:ARUK-UCL. DR GO; GO:0010468; P:regulation of gene expression; ISS:ARUK-UCL. DR GO; GO:0110089; P:regulation of hippocampal neuron apoptotic process; ISS:ARUK-UCL. DR GO; GO:0045088; P:regulation of innate immune response; ISS:ARUK-UCL. DR GO; GO:0032675; P:regulation of interleukin-6 production; ISS:ARUK-UCL. DR GO; GO:0019216; P:regulation of lipid metabolic process; IMP:ARUK-UCL. DR GO; GO:0071640; P:regulation of macrophage inflammatory protein 1 alpha production; ISS:ARUK-UCL. DR GO; GO:1903376; P:regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway; ISS:ARUK-UCL. DR GO; GO:0120035; P:regulation of plasma membrane bounded cell projection organization; IGI:ARUK-UCL. DR GO; GO:0060075; P:regulation of resting membrane potential; ISS:ARUK-UCL. DR GO; GO:0034151; P:regulation of toll-like receptor 6 signaling pathway; ISS:ARUK-UCL. DR GO; GO:0032006; P:regulation of TOR signaling; ISS:ARUK-UCL. DR GO; GO:0045728; P:respiratory burst after phagocytosis; ISS:ARUK-UCL. DR GO; GO:0048678; P:response to axon injury; IMP:ARUK-UCL. DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; IBA:GO_Central. DR GO; GO:0035176; P:social behavior; IMP:ARUK-UCL. DR GO; GO:0002291; P:T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell; IEA:Ensembl. DR DisProt; DP04132; -. DR FunFam; 2.60.40.10:FF:001076; Triggering receptor expressed on myeloid cells 2; 1. DR Gene3D; 2.60.40.10; Immunoglobulins; 1. DR InterPro; IPR036179; Ig-like_dom_sf. DR InterPro; IPR013783; Ig-like_fold. DR InterPro; IPR013106; Ig_V-set. DR InterPro; IPR052314; Immune_rcpt_domain. DR PANTHER; PTHR16423:SF11; IG-LIKE DOMAIN-CONTAINING PROTEIN; 1. DR PANTHER; PTHR16423; TREM-LIKE TRANSCRIPT PROTEIN; 1. DR Pfam; PF07686; V-set; 1. DR SUPFAM; SSF48726; Immunoglobulin; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Alzheimer disease; Amyloidosis; KW Cell membrane; Disease variant; Disulfide bond; Glycoprotein; KW Immunoglobulin domain; Lipid-binding; Membrane; Neurodegeneration; KW Proteomics identification; Receptor; Reference proteome; Secreted; Signal; KW Transmembrane; Transmembrane helix. FT SIGNAL 1..18 FT /evidence="ECO:0000255" FT CHAIN 19..230 FT /note="Triggering receptor expressed on myeloid cells 2" FT /id="PRO_0000014987" FT TOPO_DOM 19..174 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 175..195 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 196..230 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 29..112 FT /note="Ig-like V-type" FT BINDING 67 FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine" FT /ligand_id="ChEBI:CHEBI:57262" FT /evidence="ECO:0000269|PubMed:29794134, FT ECO:0007744|PDB:6B8O" FT BINDING 68 FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine" FT /ligand_id="ChEBI:CHEBI:57262" FT /evidence="ECO:0000269|PubMed:29794134, FT ECO:0007744|PDB:6B8O" FT BINDING 77 FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine" FT /ligand_id="ChEBI:CHEBI:57262" FT /evidence="ECO:0000269|PubMed:29794134, FT ECO:0007744|PDB:6B8O" FT BINDING 88 FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine" FT /ligand_id="ChEBI:CHEBI:57262" FT /evidence="ECO:0000269|PubMed:29794134, FT ECO:0007744|PDB:6B8O" FT SITE 157..158 FT /note="Cleavage of ectodomain" FT /evidence="ECO:0000269|PubMed:28855300, FT ECO:0000269|PubMed:28855301, ECO:0000269|PubMed:28923481" FT CARBOHYD 20 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:29794134, FT ECO:0007744|PDB:6B8O" FT CARBOHYD 79 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:27995897, FT ECO:0000269|PubMed:29794134, ECO:0007744|PDB:5ELI, FT ECO:0007744|PDB:6B8O" FT DISULFID 36..110 FT /evidence="ECO:0000269|PubMed:27995897, FT ECO:0000269|PubMed:29794134, ECO:0007744|PDB:5ELI, FT ECO:0007744|PDB:5UD7, ECO:0007744|PDB:5UD8, FT ECO:0007744|PDB:6B8O" FT DISULFID 51..60 FT /evidence="ECO:0000269|PubMed:27995897, FT ECO:0000269|PubMed:29794134, ECO:0007744|PDB:5ELI, FT ECO:0007744|PDB:5UD8, ECO:0007744|PDB:6B8O" FT VAR_SEQ 162..230 FT /note="SLLEGEIPFPPTSILLLLACIFLIKILAASALWAAAWHGQKPGTHPPSELDC FT GHDPGYQLQTLPGLRDT -> AERHVKEDDGRKSPGEVPPGTSPACILATWPPGLLVLL FT WQETTLPEHCFSWTLEAGTG (in isoform 2)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_010792" FT VAR_SEQ 162..230 FT /note="SLLEGEIPFPPTSILLLLACIFLIKILAASALWAAAWHGQKPGTHPPSELDC FT GHDPGYQLQTLPGLRDT -> PSQGSHLPSCLSKEPLGRRNPLPTHFHPSPPGLHLSHQ FT DSSSQRPLGCSLAWTEARDTSTQ (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_010793" FT VARIANT 14..230 FT /note="Missing (in PLOSL2; results in decreased osteoclast FT differentiation; no TREM2 transcripts can be detected in FT patient cells homozygous for the variant)" FT /evidence="ECO:0000269|PubMed:12925681" FT /id="VAR_081676" FT VARIANT 16 FT /note="S -> F (in dbSNP:rs777808487)" FT /evidence="ECO:0000269|PubMed:27589997" FT /id="VAR_090043" FT VARIANT 27 FT /note="V -> M (no effect on cell membrane localization; FT dbSNP:rs768745050)" FT /evidence="ECO:0000269|PubMed:27589997" FT /id="VAR_081812" FT VARIANT 28 FT /note="A -> V (increases cell membrane localization; FT dbSNP:rs2234252)" FT /evidence="ECO:0000269|PubMed:27589997" FT /id="VAR_081813" FT VARIANT 31 FT /note="S -> F (decreases cell membrane localization; FT dbSNP:rs746216516)" FT /evidence="ECO:0000269|PubMed:27589997" FT /id="VAR_081814" FT VARIANT 33..230 FT /note="Missing (in PLOSL2; complete loss of protein FT expression)" FT /evidence="ECO:0000269|PubMed:12754369, FT ECO:0000269|PubMed:15883308, ECO:0000269|PubMed:23399524, FT ECO:0000269|PubMed:24899047, ECO:0000269|PubMed:25615530, FT ECO:0000269|PubMed:27589997, ECO:0000269|PubMed:29142083" FT /id="VAR_081677" FT VARIANT 38 FT /note="Y -> C (results in defective protein maturation and FT trafficking; loss of proteolytic cleavage by ADAM10 and FT ectodomain shedding; increases protein aggregation; FT decreases cell membrane localization; decreased FT phagocytosis; loss of LDL, CLU and APOE binding; greatly FT decreases LDL and CLU uptake into cells; FT dbSNP:rs797044603)" FT /evidence="ECO:0000269|PubMed:24990881, FT ECO:0000269|PubMed:25615530, ECO:0000269|PubMed:27477018, FT ECO:0000269|PubMed:27589997, ECO:0000269|PubMed:27995897, FT ECO:0000269|PubMed:28768830" FT /id="VAR_081815" FT VARIANT 44..230 FT /note="Missing (in PLOSL2)" FT /evidence="ECO:0000269|PubMed:12080485" FT /id="VAR_081678" FT VARIANT 47 FT /note="R -> C (decreased cell surface expression; FT dbSNP:rs753325601)" FT /evidence="ECO:0000269|PubMed:27589997" FT /id="VAR_081816" FT VARIANT 47 FT /note="R -> H (likely risk factor for AD17; no effect on FT cell membrane localization; no effect on autophagy in FT microglia; no effect on phagocytosis, including amyloid FT plaque clearance by microglia; reduces ectodomain shedding FT caused by proteolytic cleavage by ADAM10, while also FT reducing the oligomerization of the extracellular domain FT after shedding; decreases binding to and uptake of LDL and FT CLU into cells; decreases binding to APOE, phospholipids FT and oligomeric APP cleavage product beta-amyloid peptide FT 42; dbSNP:rs75932628)" FT /evidence="ECO:0000269|PubMed:23150908, FT ECO:0000269|PubMed:24899047, ECO:0000269|PubMed:24990881, FT ECO:0000269|PubMed:25615530, ECO:0000269|PubMed:27477018, FT ECO:0000269|PubMed:27589997, ECO:0000269|PubMed:27995897, FT ECO:0000269|PubMed:28802038, ECO:0000269|PubMed:28923481, FT ECO:0000269|PubMed:29518356, ECO:0000269|PubMed:29794134, FT ECO:0000269|PubMed:30442540, ECO:0000269|PubMed:38899702" FT /id="VAR_081817" FT VARIANT 52 FT /note="R -> H (in dbSNP:rs374851046)" FT /evidence="ECO:0000269|PubMed:24899047" FT /id="VAR_090044" FT VARIANT 62 FT /note="R -> H (likely risk factor for AD17; does not affect FT protein structure; no effect on cell membrane localization; FT increases autophagy in microglia; decreases LDL, CLU and FT APOE binding; decreases LDL uptake into cells; no effect on FT CLU uptake into cells; decreases the uptake of APP-LDL FT complex in macrophages; decreases binding to oligomeric APP FT cleavage product beta-amyloid peptide 42; FT dbSNP:rs143332484)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27477018, ECO:0000269|PubMed:27995897, FT ECO:0000269|PubMed:28802038, ECO:0000269|PubMed:29518356, FT ECO:0000269|PubMed:38899702" FT /id="VAR_081818" FT VARIANT 66 FT /note="T -> M (results in defective protein maturation and FT trafficking; loss of proteolytic cleavage by ADAM10 and FT ectodomain shedding; increases protein aggregation; FT decreases cell membrane localization; decreases FT phagocytosis; loss of LDL, CLU and APOE binding; greatly FT decreases LDL and CLU uptake into cells; FT dbSNP:rs201258663)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:24990881, ECO:0000269|PubMed:25615530, FT ECO:0000269|PubMed:27477018, ECO:0000269|PubMed:27589997, FT ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:28768830" FT /id="VAR_081819" FT VARIANT 78..230 FT /note="Missing (in PLOSL2)" FT /evidence="ECO:0000269|PubMed:12080485" FT /id="VAR_081679" FT VARIANT 87 FT /note="D -> N (decreases LDL, CLU and APOE binding; FT decreases LDL and CLU uptake into cells; no effect on cell FT membrane localization; dbSNP:rs142232675)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27477018, ECO:0000269|PubMed:27589997, FT ECO:0000269|PubMed:27995897" FT /id="VAR_081820" FT VARIANT 96 FT /note="T -> K (does not change protein structure; changes FT protein stability; increases binding to THP-1 cells; FT dbSNP:rs2234253)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27995897" FT /id="VAR_061329" FT VARIANT 96 FT /note="T -> R (in dbSNP:rs2234253)" FT /id="VAR_061330" FT VARIANT 126 FT /note="V -> G (in PLOSL2; results in defective protein FT maturation; increases protein aggregation; decreases cell FT membrane localization; dbSNP:rs121908402)" FT /evidence="ECO:0000269|PubMed:15883308, FT ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:28768830" FT /id="VAR_081680" FT VARIANT 130 FT /note="A -> S (no effect on protein expression and FT maturation; dbSNP:rs759576705)" FT /evidence="ECO:0000269|PubMed:27589997" FT /id="VAR_081821" FT VARIANT 134 FT /note="D -> G (in PLOSL2; uncertain significance; decreased FT protein level; dbSNP:rs28939079)" FT /evidence="ECO:0000269|PubMed:12080485, FT ECO:0000269|PubMed:28768830" FT /id="VAR_019334" FT VARIANT 136 FT /note="R -> Q (slightly decreases cell membrane FT localization; dbSNP:rs149622783)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27589997" FT /id="VAR_081822" FT VARIANT 136 FT /note="R -> W (decreases cell membrane localization; FT dbSNP:rs772641807)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27589997" FT /id="VAR_081823" FT VARIANT 151 FT /note="E -> K (decreases cell membrane localization; FT dbSNP:rs79011726)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27589997" FT /id="VAR_081824" FT VARIANT 157 FT /note="H -> Y (accelerates ectodomain shedding but does not FT alter the cleavage site; decreases cell membrane FT localization; decreases phagocytosis; dbSNP:rs2234255)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27067662, ECO:0000269|PubMed:27589997, FT ECO:0000269|PubMed:28855300, ECO:0000269|PubMed:28855301" FT /id="VAR_033625" FT VARIANT 162 FT /note="S -> R (no effect on protein expression and FT maturation; dbSNP:rs371702633)" FT /evidence="ECO:0000269|PubMed:27589997" FT /id="VAR_081825" FT VARIANT 186 FT /note="K -> N (in PLOSL2; uncertain significance; increased FT localization at the cell membrane; dbSNP:rs28937876)" FT /evidence="ECO:0000269|PubMed:12080485, FT ECO:0000269|PubMed:28768830" FT /id="VAR_019335" FT VARIANT 192 FT /note="A -> T (in dbSNP:rs150277350)" FT /evidence="ECO:0000269|PubMed:27067662" FT /id="VAR_077696" FT VARIANT 196 FT /note="A -> T (in dbSNP:rs1345120258)" FT /evidence="ECO:0000269|PubMed:27589997" FT /id="VAR_090045" FT VARIANT 211 FT /note="L -> P (in dbSNP:rs2234256)" FT /evidence="ECO:0000269|PubMed:24899047" FT /id="VAR_033626" FT VARIANT 215 FT /note="H -> Q (in dbSNP:rs1161481912)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27589997" FT /id="VAR_090046" FT VARIANT 223 FT /note="T -> I (affects protein maturation; FT dbSNP:rs138355759)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27589997" FT /id="VAR_081826" FT MUTAGEN 20 FT /note="N->D: Loss of glycosylation." FT /evidence="ECO:0000269|PubMed:29794134" FT MUTAGEN 36 FT /note="C->A: Loss of proteolytic cleavage by ADAM10 and FT ectodomain shedding. Decreases protein maturation and cell FT membrane localization." FT /evidence="ECO:0000269|PubMed:24990881" FT MUTAGEN 48 FT /note="K->M: Loss of LDL, CLU and APOE binding." FT /evidence="ECO:0000269|PubMed:27477018" FT MUTAGEN 60 FT /note="C->A: Loss of proteolytic cleavage by ADAM10 and FT ectodomain shedding. Decreases protein maturation and cell FT membrane localization." FT /evidence="ECO:0000269|PubMed:24990881" FT MUTAGEN 68 FT /note="N->K: No effect on cell membrane localization." FT /evidence="ECO:0000269|PubMed:27995897" FT MUTAGEN 76 FT /note="R->D: Decreases binding to THP-1 cells." FT /evidence="ECO:0000269|PubMed:27995897" FT MUTAGEN 77 FT /note="R->D: Decreases binding to THP-1 cells." FT /evidence="ECO:0000269|PubMed:27995897" FT STRAND 19..27 FT /evidence="ECO:0007829|PDB:6XDS" FT STRAND 32..37 FT /evidence="ECO:0007829|PDB:6XDS" FT TURN 40..45 FT /evidence="ECO:0007829|PDB:6XDS" FT STRAND 48..53 FT /evidence="ECO:0007829|PDB:6XDS" FT TURN 55..57 FT /evidence="ECO:0007829|PDB:6XDS" FT STRAND 60..65 FT /evidence="ECO:0007829|PDB:6XDS" FT HELIX 70..72 FT /evidence="ECO:0007829|PDB:6B8O" FT STRAND 74..77 FT /evidence="ECO:0007829|PDB:6XDS" FT STRAND 80..87 FT /evidence="ECO:0007829|PDB:6XDS" FT TURN 88..91 FT /evidence="ECO:0007829|PDB:6XDS" FT STRAND 92..99 FT /evidence="ECO:0007829|PDB:6XDS" FT HELIX 102..104 FT /evidence="ECO:0007829|PDB:6XDS" FT STRAND 106..114 FT /evidence="ECO:0007829|PDB:6XDS" FT STRAND 117..129 FT /evidence="ECO:0007829|PDB:6XDS" FT HELIX 132..135 FT /evidence="ECO:0007829|PDB:6XDS" FT TURN 154..157 FT /evidence="ECO:0007829|PDB:8T51" FT HELIX 159..162 FT /evidence="ECO:0007829|PDB:8T51" FT HELIX 163..165 FT /evidence="ECO:0007829|PDB:6Z0G" FT HELIX 172..189 FT /evidence="ECO:0007829|PDB:6Z0G" FT HELIX 191..198 FT /evidence="ECO:0007829|PDB:6Z0G" FT VARIANT Q9NZC2-2:183 FT /note="S -> C (in dbSNP:rs200820365)" FT /evidence="ECO:0000269|PubMed:27067662" FT /id="VAR_082839" FT VARIANT Q9NZC2-2:191..219 FT /note="Missing" FT /evidence="ECO:0000269|PubMed:24899047" FT /id="VAR_090047" FT VARIANT Q9NZC2-2:200 FT /note="W -> C (in dbSNP:rs1391283629)" FT /evidence="ECO:0000269|PubMed:27067662" FT /id="VAR_082840" FT VARIANT Q9NZC2-2:202 FT /note="E -> D (in dbSNP:rs530314472)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27589997" FT /id="VAR_090048" SQ SEQUENCE 230 AA; 25447 MW; C894AA210F708AF7 CRC64; MEPLRLLILL FVTELSGAHN TTVFQGVAGQ SLQVSCPYDS MKHWGRRKAW CRQLGEKGPC QRVVSTHNLW LLSFLRRWNG STAITDDTLG GTLTITLRNL QPHDAGLYQC QSLHGSEADT LRKVLVEVLA DPLDHRDAGD LWFPGESESF EDAHVEHSIS RSLLEGEIPF PPTSILLLLA CIFLIKILAA SALWAAAWHG QKPGTHPPSE LDCGHDPGYQ LQTLPGLRDT // ID TTC3_HUMAN Reviewed; 2025 AA. AC P53804; A8K7H7; B2RPA7; D3DSG9; D3DSH2; D3DSH3; O60767; P78476; P78477; AC Q569I2; Q6P578; Q9UEK4; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 30-NOV-2010, sequence version 2. DT 28-JAN-2026, entry version 215. DE RecName: Full=E3 ubiquitin-protein ligase TTC3; DE EC=2.3.2.27 {ECO:0000269|PubMed:20059950, ECO:0000269|PubMed:30696809}; DE AltName: Full=Protein DCRR1; DE AltName: Full=RING finger protein 105; DE AltName: Full=RING-type E3 ubiquitin transferase TTC3 {ECO:0000305}; DE AltName: Full=TPR repeat protein D; DE AltName: Full=Tetratricopeptide repeat protein 3; DE Short=TPR repeat protein 3; GN Name=TTC3; Synonyms=DCRR1, RNF105, TPRD; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM TPRDI), AND VARIANT HIS-1751. RC TISSUE=Brain; RX PubMed=8724848; DOI=10.1093/dnares/3.1.9; RA Ohira M., Ootsuyama A., Suzuki E., Ichikawa H., Seki N., Nagase T., RA Nomura N., Ohki M.; RT "Identification of a novel human gene containing the tetratricopeptide RT repeat domain from the Down syndrome region of chromosome 21."; RL DNA Res. 3:9-16(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS TPRDI; TPRDII AND TPRDIII), AND RP VARIANT HIS-1751. RC TISSUE=Fetal brain, and Placenta; RX PubMed=8947847; DOI=10.1093/oxfordjournals.jbchem.a021485; RA Tsukahara F., Hattori M., Muraki T., Sakaki Y.; RT "Identification and cloning of a novel cDNA belonging to tetratricopeptide RT repeat gene family from Down syndrome-critical region 21q22.2."; RL J. Biochem. 120:820-827(1996). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=10830953; DOI=10.1038/35012518; RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S., RA Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M., RA Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A., Menzel U., RA Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A., RA Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J., RA Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K., RA Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G., RA Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J., RA Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S., RA Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K., RA Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L.; RT "The DNA sequence of human chromosome 21."; RL Nature 405:311-319(2000). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM TPRDI). RC TISSUE=Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-627 (ISOFORM TPRDI). RC TISSUE=Small intestine; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 85-2025 (ISOFORM TPRDI), AND VARIANT THR-840. RX PubMed=9254009; DOI=10.3109/10425179709034031; RA Eki T., Abe M., Naitou M., Sasanuma S.I., Nohata J., Kawashima K., RA Ahmad I., Hanaoka F., Murakami Y.; RT "Cloning and characterization of novel gene, DCRR1, expressed from Down's RT syndrome critical region of human chromosome 21q22.2."; RL DNA Seq. 7:153-164(1997). RN [8] RP NUCLEOTIDE SEQUENCE [MRNA] OF 121-616 (ISOFORM TPRDI). RC TISSUE=Fetal brain; RX PubMed=9503011; DOI=10.1006/geno.1997.5146; RA Dahmane N., Ait-Ghezala G., Gosset P., Chamoun Z., Dufresne-Zacharia M.-C., RA Lopes C., Rabatel N., Gassanova-Maugenre S., Chettouh Z., Abramowski V., RA Fayet E., Yaspo M.-L., Korn B., Blouin J.-L., Lehrach H., Poustka A., RA Antonarakis S.E., Sinet P.-M., Creau N., Delabar J.-M.; RT "Transcriptional map of the 2.5-Mb CBR-ERG region of chromosome 21 involved RT in Down syndrome."; RL Genomics 48:12-23(1998). RN [9] RP FUNCTION, AND INTERACTION WITH CIT. RX PubMed=17488780; DOI=10.1242/jcs.000703; RA Berto G., Camera P., Fusco C., Imarisio S., Ambrogio C., Chiarle R., RA Silengo L., Di Cunto F.; RT "The Down syndrome critical region protein TTC3 inhibits neuronal RT differentiation via RhoA and Citron kinase."; RL J. Cell Sci. 120:1859-1867(2007). RN [10] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, SUBCELLULAR LOCATION, INTERACTION RP WITH AKT1; AKT2 AND AKT3, PHOSPHORYLATION AT SER-378, AND MUTAGENESIS OF RP SER-378. RX PubMed=20059950; DOI=10.1016/j.devcel.2009.09.007; RA Suizu F., Hiramuki Y., Okumura F., Matsuda M., Okumura A.J., Hirata N., RA Narita M., Kohno T., Yokota J., Bohgaki M., Obuse C., Hatakeyama S., RA Obata T., Noguchi M.; RT "The E3 ligase TTC3 facilitates ubiquitination and degradation of RT phosphorylated Akt."; RL Dev. Cell 17:800-810(2009). RN [11] RP FUNCTION. RX PubMed=24695496; DOI=10.1371/journal.pone.0093721; RA Berto G.E., Iobbi C., Camera P., Scarpa E., Iampietro C., Bianchi F., RA Gai M., Sgro F., Cristofani F., Gaertner A., Dotti C.G., Di Cunto F.; RT "The DCR protein TTC3 affects differentiation and Golgi compactness in RT neurons through specific actin-regulating pathways."; RL PLoS ONE 9:E93721-E93721(2014). RN [12] RP INTERACTION WITH POLG AND HSP70. RX PubMed=29290964; DOI=10.18632/oncotarget.22476; RA Gong Y., Wang X., Shang X., Xiao S.P., Li W., Shang Y., Dou F.; RT "Tetratricopeptide repeat domain 3 overexpression tends to form aggregates RT and inhibit ubiquitination and degradation of DNA polymerase gamma."; RL Oncotarget 8:106475-106485(2017). RN [13] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, INTERACTION WITH SMURF2, AND RP INDUCTION BY TGFB1. RX PubMed=30696809; DOI=10.1038/s41419-019-1308-8; RA Kim J.H., Ham S., Lee Y., Suh G.Y., Lee Y.S.; RT "TTC3 contributes to TGF-beta1-induced epithelial-mesenchymal transition RT and myofibroblast differentiation, potentially through SMURF2 RT ubiquitylation and degradation."; RL Cell Death Dis. 10:92-92(2019). RN [14] RP FUNCTION, SUBCELLULAR LOCATION, AND PROTEOLYTIC CLEAVAGE. RX PubMed=30203323; DOI=10.1007/s12017-018-8509-7; RA Gong Y., Wang K., Xiao S.P., Mi P., Li W., Shang Y., Dou F.; RT "Overexpressed TTC3 Protein Tends to be Cleaved into Fragments and Form RT Aggregates in the Nucleus."; RL NeuroMolecular Med. 21:85-96(2019). RN [15] RP VARIANT [LARGE SCALE ANALYSIS] MET-1289. 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 [16] RP VARIANT CYS-1038. RX PubMed=27066578; DOI=10.1212/nxg.0000000000000041; RA Kohli M.A., Cukier H.N., Hamilton-Nelson K.L., Rolati S., Kunkle B.W., RA Whitehead P.L., Zuechner S.L., Farrer L.A., Martin E.R., Beecham G.W., RA Haines J.L., Vance J.M., Cuccaro M.L., Gilbert J.R., Schellenberg G.D., RA Carney R.M., Pericak-Vance M.A.; RT "Segregation of a rare TTC3 variant in an extended family with late-onset RT Alzheimer disease."; RL Neurol. Genet. 2:E41-E41(2016). CC -!- FUNCTION: E3 ubiquitin-protein ligase which catalyzes the formation of CC 'Lys-48'-polyubiquitin chains (PubMed:20059950, PubMed:30696809). CC Mediates the ubiquitination and subsequent degradation of CC phosphorylated Akt (AKT1, AKT2 and AKT3) in the nucleus CC (PubMed:20059950). Acts as a terminal regulator of Akt signaling after CC activation; its phosphorylation by Akt, which is a prerequisite for CC ubiquitin ligase activity, suggests the existence of a regulation CC mechanism required to control Akt levels after activation CC (PubMed:20059950). Positively regulates TGFB1-induced epithelial- CC mesenchymal transition and myofibroblast differentiation by mediating CC the ubiquitination and subsequent degradation of SMURF2 CC (PubMed:30696809). Regulates neuronal differentiation by regulating CC actin remodeling and Golgi organization via a signaling cascade CC involving RHOA, CIT and ROCK (PubMed:17488780, PubMed:24695496). CC Inhibits cell proliferation (PubMed:30203323). CC {ECO:0000269|PubMed:17488780, ECO:0000269|PubMed:20059950, CC ECO:0000269|PubMed:24695496, ECO:0000269|PubMed:30203323, CC ECO:0000269|PubMed:30696809}. CC -!- CATALYTIC ACTIVITY: CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; CC EC=2.3.2.27; Evidence={ECO:0000269|PubMed:20059950, CC ECO:0000269|PubMed:30696809}; CC -!- PATHWAY: Protein modification; protein ubiquitination. CC {ECO:0000269|PubMed:20059950, ECO:0000269|PubMed:30696809}. CC -!- SUBUNIT: Interacts (when phosphorylated on Ser-378) with AKT1, AKT2 and CC AKT3 (when phosphorylated) (PubMed:20059950). Interacts with CIT CC (PubMed:17488780). Interacts with POLG (PubMed:29290964). Interacts CC with HSP70 (PubMed:29290964). Interacts with SMURF2 (PubMed:30696809). CC {ECO:0000269|PubMed:17488780, ECO:0000269|PubMed:20059950, CC ECO:0000269|PubMed:29290964, ECO:0000269|PubMed:30696809}. CC -!- INTERACTION: CC P53804; P31749: AKT1; NbExp=4; IntAct=EBI-2681313, EBI-296087; CC P53804; P31751: AKT2; NbExp=5; IntAct=EBI-2681313, EBI-296058; CC P53804; Q9Y243: AKT3; NbExp=2; IntAct=EBI-2681313, EBI-296115; CC P53804; Q9HAU4: SMURF2; NbExp=2; IntAct=EBI-2681313, EBI-396727; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:20059950, CC ECO:0000269|PubMed:30203323}. Cytoplasm {ECO:0000269|PubMed:30203323}. CC Golgi apparatus {ECO:0000250|UniProtKB:D3ZSP7}. Note=Nuclear CC localization may be dependent on the proteolytic cleavage of full CC length protein in the cytoplasm (PubMed:30203323). This cleavage may CC reveal an N-terminal nuclear localization signal, allowing N-terminal CC fragments to enter the nucleus (PubMed:30203323). CC {ECO:0000269|PubMed:30203323}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=TPRDI; CC IsoId=P53804-1; Sequence=Displayed; CC Name=TPRDII; CC IsoId=P53804-2; Sequence=VSP_006554; CC Name=TPRDIII; CC IsoId=P53804-3; Sequence=VSP_006555; CC -!- TISSUE SPECIFICITY: Found in all tissues examined. CC -!- INDUCTION: Up-regulated by TGFB1 signaling. CC {ECO:0000269|PubMed:30696809}. CC -!- PTM: Phosphorylation on Ser-378 by Akt is required for ubiquitin ligase CC activity. {ECO:0000269|PubMed:20059950}. CC -!- PTM: Proteolytically cleaved into differently sized N- and C-terminal CC fragments. {ECO:0000269|PubMed:30203323}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH63033.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; CC Sequence=AAH92466.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={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; D83077; BAA11769.1; -; mRNA. DR EMBL; D84294; BAA12301.1; -; mRNA. DR EMBL; D84295; BAA12302.1; -; mRNA. DR EMBL; D84296; BAA12303.1; -; mRNA. DR EMBL; AP001429; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP001432; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471079; EAX09716.1; -; Genomic_DNA. DR EMBL; CH471079; EAX09717.1; -; Genomic_DNA. DR EMBL; CH471079; EAX09718.1; -; Genomic_DNA. DR EMBL; CH471079; EAX09719.1; -; Genomic_DNA. DR EMBL; CH471079; EAX09720.1; -; Genomic_DNA. DR EMBL; CH471079; EAX09721.1; -; Genomic_DNA. DR EMBL; CH471079; EAX09722.1; -; Genomic_DNA. DR EMBL; CH471079; EAX09723.1; -; Genomic_DNA. DR EMBL; BC063033; AAH63033.1; ALT_SEQ; mRNA. DR EMBL; BC092466; AAH92466.1; ALT_SEQ; mRNA. DR EMBL; BC137345; AAI37346.1; -; mRNA. DR EMBL; AK291992; BAF84681.1; -; mRNA. DR EMBL; D83327; BAA23666.1; -; mRNA. DR EMBL; AJ001866; CAA05057.1; -; mRNA. DR CCDS; CCDS13651.1; -. [P53804-1] DR CCDS; CCDS93096.1; -. [P53804-3] DR PIR; JC5020; JC5020. DR RefSeq; NP_001001894.1; NM_001001894.3. [P53804-1] DR RefSeq; NP_001307633.1; NM_001320704.1. DR RefSeq; NP_001317610.1; NM_001330681.2. [P53804-3] DR RefSeq; NP_001317611.1; NM_001330682.2. [P53804-3] DR RefSeq; NP_001317612.1; NM_001330683.2. [P53804-1] DR RefSeq; NP_001340865.1; NM_001353936.2. [P53804-3] DR RefSeq; NP_003307.3; NM_003316.3. [P53804-1] DR AlphaFoldDB; P53804; -. DR BioGRID; 113118; 135. DR ELM; P53804; -. DR FunCoup; P53804; 3414. DR IntAct; P53804; 110. DR MINT; P53804; -. DR STRING; 9606.ENSP00000381981; -. DR GlyGen; P53804; 1 site. DR iPTMnet; P53804; -. DR PhosphoSitePlus; P53804; -. DR BioMuta; TTC3; -. DR DMDM; 313104040; -. DR jPOST; P53804; -. DR MassIVE; P53804; -. DR PaxDb; 9606-ENSP00000381981; -. DR PeptideAtlas; P53804; -. DR ProteomicsDB; 56623; -. [P53804-1] DR ProteomicsDB; 56624; -. [P53804-2] DR ProteomicsDB; 56625; -. [P53804-3] DR Pumba; P53804; -. DR Antibodypedia; 8442; 69 antibodies from 19 providers. DR DNASU; 7267; -. DR Ensembl; ENST00000354749.6; ENSP00000346791.2; ENSG00000182670.14. [P53804-1] DR Ensembl; ENST00000399017.6; ENSP00000381981.2; ENSG00000182670.14. [P53804-1] DR Ensembl; ENST00000418766.6; ENSP00000403943.2; ENSG00000182670.14. [P53804-1] DR Ensembl; ENST00000450533.6; ENSP00000408456.2; ENSG00000182670.14. [P53804-1] DR Ensembl; ENST00000463216.6; ENSP00000512893.1; ENSG00000182670.14. [P53804-3] DR Ensembl; ENST00000492275.6; ENSP00000512889.1; ENSG00000182670.14. [P53804-3] DR GeneID; 7267; -. DR KEGG; hsa:7267; -. DR MANE-Select; ENST00000418766.6; ENSP00000403943.2; NM_001330683.2; NP_001317612.1. DR UCSC; uc002yvz.4; human. [P53804-1] DR AGR; HGNC:12393; -. DR ClinPGx; PA37058; -. DR CTD; 7267; -. DR DisGeNET; 7267; -. DR GeneCards; TTC3; -. DR HGNC; HGNC:12393; TTC3. DR HPA; ENSG00000182670; Low tissue specificity. DR MIM; 602259; gene. DR OpenTargets; ENSG00000182670; -. DR VEuPathDB; HostDB:ENSG00000182670; -. DR eggNOG; KOG0800; Eukaryota. DR GeneTree; ENSGT00940000154465; -. DR HOGENOM; CLU_001829_1_0_1; -. DR InParanoid; P53804; -. DR OMA; CEDVRAK; -. DR OrthoDB; 8062037at2759; -. DR PAN-GO; P53804; 2 GO annotations based on evolutionary models. DR PhylomeDB; P53804; -. DR PathwayCommons; P53804; -. DR SignaLink; P53804; -. DR SIGNOR; P53804; -. DR UniPathway; UPA00143; -. DR Agora; ENSG00000182670; -. DR BioGRID-ORCS; 7267; 10 hits in 1195 CRISPR screens. DR ChiTaRS; TTC3; human. DR GeneWiki; TTC3; -. DR GenomeRNAi; 7267; -. DR Pharos; P53804; Tbio. DR PRO; PR:P53804; -. DR Proteomes; UP000005640; Chromosome 21. DR RNAct; P53804; protein. DR Bgee; ENSG00000182670; Expressed in cortical plate and 210 other cell types or tissues. DR ExpressionAtlas; P53804; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell. DR GO; GO:0005730; C:nucleolus; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IEA:UniProtKB-EC. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW. DR GO; GO:0070936; P:protein K48-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:UniProtKB. DR CDD; cd16481; RING-H2_TTC3; 1. DR FunFam; 1.25.40.10:FF:000370; E3 ubiquitin-protein ligase TTC3; 1. DR FunFam; 1.25.40.10:FF:000143; E3 ubiquitin-protein ligase TTC3 isoform X2; 1. DR FunFam; 3.30.40.10:FF:000529; Tetratricopeptide repeat domain 3; 1. DR Gene3D; 1.10.533.10; Death Domain, Fas; 1. DR Gene3D; 1.25.40.10; Tetratricopeptide repeat domain; 2. DR Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 1. DR InterPro; IPR011029; DEATH-like_dom_sf. DR InterPro; IPR011990; TPR-like_helical_dom_sf. DR InterPro; IPR019734; TPR_rpt. DR InterPro; IPR056872; TTC3/DZIP3-like_helical. DR InterPro; IPR056870; TTC3/DZIP3/RBM44-like_helical. DR InterPro; IPR043866; TTC3/DZIP3_dom. DR InterPro; IPR056871; WH_TTC3. DR InterPro; IPR001841; Znf_RING. DR InterPro; IPR013083; Znf_RING/FYVE/PHD. DR PANTHER; PTHR17550; E3 UBIQUITIN-PROTEIN LIGASE TTC3; 1. DR PANTHER; PTHR17550:SF6; E3 UBIQUITIN-PROTEIN LIGASE TTC3; 1. DR Pfam; PF24525; TTC3; 1. DR Pfam; PF24905; TTC3_9th; 1. DR Pfam; PF19179; TTC3_DZIP3_dom; 1. DR Pfam; PF24812; WHD_TTC3; 1. DR Pfam; PF13639; zf-RING_2; 1. DR SMART; SM00184; RING; 1. DR SMART; SM00028; TPR; 4. DR SUPFAM; SSF57850; RING/U-box; 1. DR SUPFAM; SSF48452; TPR-like; 2. DR PROSITE; PS50005; TPR; 2. DR PROSITE; PS50293; TPR_REGION; 2. DR PROSITE; PS50089; ZF_RING_2; 1. PE 1: Evidence at protein level; KW Alternative splicing; Cytoplasm; Golgi apparatus; Metal-binding; Nucleus; KW Phosphoprotein; Proteomics identification; Reference proteome; Repeat; KW TPR repeat; Transferase; Ubl conjugation pathway; Zinc; Zinc-finger. FT CHAIN 1..2025 FT /note="E3 ubiquitin-protein ligase TTC3" FT /id="PRO_0000106378" FT REPEAT 231..264 FT /note="TPR 1" FT REPEAT 266..298 FT /note="TPR 2" FT REPEAT 536..572 FT /note="TPR 3" FT REPEAT 576..609 FT /note="TPR 4" FT ZN_FING 1957..1997 FT /note="RING-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175" FT REGION 1..230 FT /note="Interaction with POLG" FT /evidence="ECO:0000269|PubMed:29290964" FT REGION 423..458 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 786..805 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1012..1068 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1215..1295 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1773..1842 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1894..1944 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 2004..2025 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 793..805 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1019..1029 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1038..1052 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1894..1912 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1913..1928 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 2013..2025 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 378 FT /note="Phosphoserine; by PKB/AKT2" FT /evidence="ECO:0000269|PubMed:20059950" FT MOD_RES 1009 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O88196" FT MOD_RES 1061 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O88196" FT VAR_SEQ 1..310 FT /note="Missing (in isoform TPRDIII)" FT /evidence="ECO:0000303|PubMed:8947847" FT /id="VSP_006555" FT VAR_SEQ 1..233 FT /note="Missing (in isoform TPRDII)" FT /evidence="ECO:0000303|PubMed:8947847" FT /id="VSP_006554" FT VARIANT 840 FT /note="M -> T (in dbSNP:rs1053808)" FT /evidence="ECO:0000269|PubMed:9254009" FT /id="VAR_020312" FT VARIANT 1038 FT /note="S -> C (in an extended family with high risk of FT late-onset Alzheimer Disease; dbSNP:rs377155188)" FT /evidence="ECO:0000269|PubMed:27066578" FT /id="VAR_082645" FT VARIANT 1154 FT /note="P -> S (in dbSNP:rs1053840)" FT /id="VAR_044428" FT VARIANT 1289 FT /note="K -> M (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_035868" FT VARIANT 1751 FT /note="D -> H (in dbSNP:rs1053966)" FT /evidence="ECO:0000269|PubMed:8724848, FT ECO:0000269|PubMed:8947847" FT /id="VAR_024676" FT MUTAGEN 378 FT /note="S->A: Abolishes phosphorylation by Akt and impairs FT ubiquitin ligase activity on Akt." FT /evidence="ECO:0000269|PubMed:20059950" FT CONFLICT 9 FT /note="F -> Y (in Ref. 5; AAH92466)" FT /evidence="ECO:0000305" FT CONFLICT 121 FT /note="N -> D (in Ref. 8; CAA05057)" FT /evidence="ECO:0000305" FT CONFLICT 139 FT /note="K -> R (in Ref. 8; CAA05057)" FT /evidence="ECO:0000305" FT CONFLICT 232 FT /note="E -> G (in Ref. 8; CAA05057)" FT /evidence="ECO:0000305" FT CONFLICT 276 FT /note="L -> P (in Ref. 8; CAA05057)" FT /evidence="ECO:0000305" FT CONFLICT 437 FT /note="K -> Q (in Ref. 5; AAH63033)" FT /evidence="ECO:0000305" FT CONFLICT 495 FT /note="Q -> P (in Ref. 7; BAA23666)" FT /evidence="ECO:0000305" FT CONFLICT 1700 FT /note="E -> V (in Ref. 7; BAA23666)" FT /evidence="ECO:0000305" FT CONFLICT 1822 FT /note="A -> T (in Ref. 7; BAA23666)" FT /evidence="ECO:0000305" SQ SEQUENCE 2025 AA; 229869 MW; C80BC8E1970B6725 CRC64; MDNFAEGDFT VADYALLEDC PHVDDCVFAA EFMSNDYVRV TQLYCDGVGV QYKDYIQSER NLEFDICSIW CSKPISVLQD YCDAIKINIF WPLLFQHQNS SVISRLHPCV DANNSRASEI NLKKLQHLEL MEDIVDLAKK VANDSFLIGG LLRIGCKIEN KILAMEEALN WIKYAGDVTI LTKLGSIDNC WPMLSIFFTE YKYHITKIVM EDCNLLEELK TQSCMDCIEE GELMKMKGNE EFSKERFDIA IIYYTRAIEY RPENYLLYGN RALCFLRTGQ FRNALGDGKR ATILKNTWPK GHYRYCDALS MLGEYDWALQ ANIKAQKLCK NDPEGIKDLI QQHVKLQKQI EDLQGRTANK DPIKAFYENR AYTPRSLSAP IFTTSLNFVE KERDFRKINH EMANGGNQNL KVADEALKVD DCDCHPEFSP PSSQPPKHKG KQKSRNNESE KFSSSSPLTL PADLKNILEK QFSKSSRAAH QDFANIMKML RSLIQDGYMA LLEQRCRSAA QAFTELLNGL DPQKIKQLNL AMINYVLVVY GLAISLLGIG QPEELSEAEN QFKRIIEHYP SEGLDCLAYC GIGKVYLKKN RFLEALNHFE KARTLIYRLP GVLTWPTSNV IIEESQPQKI KMLLEKFVEE CKFPPVPDAI CCYQKCHGYS KIQIYITDPD FKGFIRISCC QYCKIEFHMN CWKKLKTTTF NDKIDKDFLQ GICLTPDCEG VISKIIIFSS GGEVKCEFEH KVIKEKVPPR PILKQKCSSL EKLRLKEDKK LKRKIQKKEA KKLAQERMEE DLRESNPPKN EEQKETVDNV QRCQFLDDRI LQCIKQYADK IKSGIQNTAM LLKELLSWKV LSTEDYTTCF SSRNFLNEAV DYVIRHLIQE NNRVKTRIFL HVLSELKEVE PKLAAWIQKL NSFGLDATGT FFSRYGASLK LLDFSIMTFL WNEKYGHKLD SIEGKQLDYF SEPASLKEAR CLIWLLEEHR DKFPALHSAL DEFFDIMDSR CTVLRKQDSG EAPFSSTKVK NKSKKKKPKD SKPMLVGSGT TSVTSNNEII TSSEDHSNRN SDSAGPFAVP DHLRQDVEEF EALYDQHSNE YVVRNKKLWD MNPKQKCSTL YDYFSQFLEE HGPLDMSNKM FSAEYEFFPE ETRQILEKAG GLKPFLLGCP RFVVIDNCIA LKKVASRLKK KRKKKNIKTK VEEISKAGEY VRVKLQLNPA AREFKPDVKS KPVSDSSSAP AFENVKPKPV SANSPKPACE DVKAKPVSDN SSRQVSEDGQ PKGVSSNSPK PGSEDANYKR VSCNSPKPVL EDVKPTYWAQ SHLVTGYCTY LPFQRFDITQ TPPAYINVLP GLPQYTSIYT PLASLSPEYQ LPRSVPVVPS FVANDRADKN AAAYFEGHHL NAENVAGHQI ASETQILEGS LGISVKSHCS TGDAHTVLSE SNRNDEHCGN SNNKCEVIPE STSAVTNIPH VQMVAIQVSW NIIHQEVNTE PYNPFEERQG EISRIEKEHQ VLQDQLQEVY ENYEQIKLKG LEETRDLEEK LKRHLEENKI SKTELDWFLQ DLEREIKKWQ QEKKEIQERL KSLKKKIKKV SNASEMYTQK NDGKEKEHEL HLDQSLEISN TLTNEKMKIE EYIKKGKEDY EESHQRAVAA EVSVLENWKE SEVYKLQIME SQAEAFLKKL GLISRDPAAY PDMESDIRSW ELFLSNVTKE IEKAKSQFEE QIKAIKNGSR LSELSKVQIS ELSFPACNTV HPELLPESSG DDGQGLVTSA SDVTGNHAAL HRDPSVFSAG DSPGEAPSAL LPGPPPGQPE ATQLTGPKRA GQAALSERSP VADRKQPVPP GRAARSSQSP KKPFNSIIEH LSVVFPCYNS TELAGFIKKV RSKNKNSLSG LSIDEIVQRV TEHILDEQKK KKPNPGKDKR TYEPSSATPV TRSSQGSPSV VVAPSPKTKG QKAEDVPVRI ALGASSCEIC HEVFKSKNVR VLKCGHKYHK GCFKQWLKGQ SACPACQGRD LLTEESPSGR GWPSQNQELP SCSSR // ID UCHL1_HUMAN Reviewed; 223 AA. AC P09936; Q4W5K6; Q71UM0; DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1990, sequence version 2. DT 28-JAN-2026, entry version 248. DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase isozyme L1; DE Short=UCH-L1; DE EC=3.4.19.12 {ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:16475834, ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}; DE AltName: Full=Neuron cytoplasmic protein 9.5; DE AltName: Full=PGP 9.5; DE Short=PGP9.5; DE AltName: Full=Ubiquitin thioesterase L1; DE Flags: Precursor; GN Name=UCHL1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lung, and Muscle; 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 [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-15. RX PubMed=2163617; DOI=10.1042/bj2680521; RA Day I.N.M., Hinks L.J., Thompson R.J.; RT "The structure of the human gene encoding protein gene product 9.5 RT (PGP9.5), a neuron-specific ubiquitin C-terminal hydrolase."; RL Biochem. J. 268:521-524(1990). RN [5] RP PROTEIN SEQUENCE OF 1-15 AND 214-221, SUSCEPTIBILITY TO OXIDATION, RP IDENTIFICATION BY MASS SPECTROMETRY, AND TISSUE SPECIFICITY. RX PubMed=14722078; DOI=10.1074/jbc.m314124200; RA Choi J., Levey A.I., Weintraub S.T., Rees H.D., Gearing M., Chin L.-S., RA Li L.; RT "Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal RT hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's RT diseases."; RL J. Biol. Chem. 279:13256-13264(2004). RN [6] RP PROTEIN SEQUENCE OF 1-15; 20-27; 66-78; 84-129; 136-195 AND 214-221, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex; RA Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y.; RL Submitted (DEC-2008) to UniProtKB. RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 7-223, AND PARTIAL PROTEIN SEQUENCE. RX PubMed=2947814; DOI=10.1016/0014-5793(87)81327-3; RA Day I.N.M., Thompson R.J.; RT "Molecular cloning of cDNA coding for human PGP 9.5 protein. A novel RT cytoplasmic marker for neurones and neuroendocrine cells."; RL FEBS Lett. 210:157-160(1987). RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 16-223, FUNCTION, CATALYTIC ACTIVITY, RP BIOPHYSICOCHEMICAL PROPERTIES, VARIANT PARK5 MET-93, AND CHARACTERIZATION RP OF VARIANT PARK5 MET-93. RX PubMed=9774100; DOI=10.1038/26652; RA Leroy E., Boyer R., Auburger G., Leube B., Ulm G., Mezey E., Harta G., RA Brownstein M.J., Jonnalagada S., Chernova T., Dehejia A., Lavedan C., RA Gasser T., Steinbach P.J., Wilkinson K.D., Polymeropoulos M.H.; RT "The ubiquitin pathway in Parkinson's disease."; RL Nature 395:451-452(1998). RN [9] RP PROTEIN SEQUENCE OF 20-25; 79-81; 106-121 AND 134-151. RX PubMed=1849484; DOI=10.1016/0014-5793(91)80300-r; RA Honore B., Rasmussen H.H., Vandekerckhove J., Celis J.E.; RT "Neuronal protein gene product 9.5 (IEF SSP 6104) is expressed in cultured RT human MRC-5 fibroblasts of normal origin and is strongly down-regulated in RT their SV40 transformed counterparts."; RL FEBS Lett. 280:235-240(1991). RN [10] RP PROTEIN SEQUENCE OF 20-25; 79-91; 106-123 AND 136-151. RX PubMed=1286667; DOI=10.1002/elps.11501301199; RA Rasmussen H.H., van Damme J., Puype M., Gesser B., Celis J.E., RA Vandekerckhove J.; RT "Microsequences of 145 proteins recorded in the two-dimensional gel protein RT database of normal human epidermal keratinocytes."; RL Electrophoresis 13:960-969(1992). RN [11] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, MUTAGENESIS OF GLN-73; CYS-90; RP HIS-97; HIS-161 AND ASP-176, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=8639624; DOI=10.1021/bi960099f; RA Larsen C.N., Price J.S., Wilkinson K.D.; RT "Substrate binding and catalysis by ubiquitin C-terminal hydrolases: RT identification of two active site residues."; RL Biochemistry 35:6735-6744(1996). RN [12] RP TISSUE SPECIFICITY. RX PubMed=9790970; DOI=10.1006/bbrc.1998.9532; RA Wada H., Kito K., Caskey L.S., Yeh E.T.H., Kamitani T.; RT "Cleavage of the C-terminus of NEDD8 by UCH-L3."; RL Biochem. Biophys. Res. Commun. 251:688-692(1998). RN [13] RP FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANT PARK5 MET-93, AND RP CHARACTERIZATION OF VARIANT TYR-18. RX PubMed=12408865; DOI=10.1016/s0092-8674(02)01012-7; RA Liu Y., Fallon L., Lashuel H.A., Liu Z., Lansbury P.T. Jr.; RT "The UCH-L1 gene encodes two opposing enzymatic activities that affect RT alpha-synuclein degradation and Parkinson's disease susceptibility."; RL Cell 111:209-218(2002). RN [14] RP INTERACTION WITH COPS5. RX PubMed=12082530; DOI=10.1038/sj.onc.1205390; RA Caballero O.L., Resto V., Patturajan M., Meerzaman D., Guo M.Z., Engles J., RA Yochem R., Ratovitski E., Sidransky D., Jen J.; RT "Interaction and colocalization of PGP9.5 with JAB1 and p27(Kip1)."; RL Oncogene 21:3003-3010(2002). RN [15] RP CATALYTIC ACTIVITY, AND ACTIVE SITE. RX PubMed=16475834; DOI=10.1021/bi052135t; RA Case A., Stein R.L.; RT "Mechanistic studies of ubiquitin C-terminal hydrolase L1."; RL Biochemistry 45:2443-2452(2006). RN [16] RP SUBCELLULAR LOCATION, AND ISOPRENYLATION AT CYS-220. RX PubMed=19261853; DOI=10.1073/pnas.0806474106; RA Liu Z., Meray R.K., Grammatopoulos T.N., Fredenburg R.A., Cookson M.R., RA Liu Y., Logan T., Lansbury P.T. Jr.; RT "Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein RT neurotoxicity and is a therapeutic target for Parkinson's disease."; RL Proc. Natl. Acad. Sci. U.S.A. 106:4635-4640(2009). RN [17] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [18] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [19] RP FUNCTION. RX PubMed=22212137; DOI=10.1111/j.1471-4159.2011.07644.x; RA Zhang M., Deng Y., Luo Y., Zhang S., Zou H., Cai F., Wada K., Song W.; RT "Control of BACE1 degradation and APP processing by ubiquitin carboxyl- RT terminal hydrolase L1."; RL J. Neurochem. 120:1129-1138(2012). RN [20] RP FUNCTION, CATALYTIC ACTIVITY, VARIANTS SPG79B ALA-7 AND MET-93, RP CHARACTERIZATION OF VARIANT SPG79B ALA-7, AND MUTAGENESIS OF CYS-90. RX PubMed=23359680; DOI=10.1073/pnas.1222732110; RA Bilguvar K., Tyagi N.K., Ozkara C., Tuysuz B., Bakircioglu M., Choi M., RA Delil S., Caglayan A.O., Baranoski J.F., Erturk O., Yalcinkaya C., RA Karacorlu M., Dincer A., Johnson M.H., Mane S., Chandra S.S., Louvi A., RA Boggon T.J., Lifton R.P., Horwich A.L., Gunel M.; RT "Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads RT to early-onset progressive neurodegeneration."; RL Proc. Natl. Acad. Sci. U.S.A. 110:3489-3494(2013). RN [21] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF CYS-90. RX PubMed=25615526; DOI=10.1038/ncomms7153; RA Goto Y., Zeng L., Yeom C.J., Zhu Y., Morinibu A., Shinomiya K., RA Kobayashi M., Hirota K., Itasaka S., Yoshimura M., Tanimoto K., Torii M., RA Sowa T., Menju T., Sonobe M., Kakeya H., Toi M., Date H., Hammond E.M., RA Hiraoka M., Harada H.; RT "UCHL1 provides diagnostic and antimetastatic strategies due to its RT deubiquitinating effect on HIF-1alpha."; RL Nat. Commun. 6:6153-6153(2015). RN [22] RP IDENTIFICATION BY MASS SPECTROMETRY (ISOFORMS 2 AND 3), AND ACETYLATION AT RP MET-1 (ISOFORMS 1; 2 AND 3). RX PubMed=37316325; DOI=10.26508/lsa.202301972; RA Bogaert A., Fijalkowska D., Staes A., Van de Steene T., Vuylsteke M., RA Stadler C., Eyckerman S., Spirohn K., Hao T., Calderwood M.A., Gevaert K.; RT "N-terminal proteoforms may engage in different protein complexes."; RL Life. Sci Alliance 6:0-0(2023). RN [23] RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS), AND SUBUNIT. RX PubMed=16537382; DOI=10.1073/pnas.0510403103; RA Das C., Hoang Q.Q., Kreinbring C.A., Luchansky S.J., Meray R.K., Ray S.S., RA Lansbury P.T., Ringe D., Petsko G.A.; RT "Structural basis for conformational plasticity of the Parkinson's disease- RT associated ubiquitin hydrolase UCH-L1."; RL Proc. Natl. Acad. Sci. U.S.A. 103:4675-4680(2006). RN [24] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF VARIANTS TYR-18 AND MET-93 IN RP COMPLEX WITH UBIQUITIN, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF RP CYS-90 AND PHE-204. RX PubMed=20439756; DOI=10.1073/pnas.0910870107; RA Boudreaux D.A., Maiti T.K., Davies C.W., Das C.; RT "Ubiquitin vinyl methyl ester binding orients the misaligned active site of RT the ubiquitin hydrolase UCHL1 into productive conformation."; RL Proc. Natl. Acad. Sci. U.S.A. 107:9117-9122(2010). RN [25] RP CHARACTERIZATION OF VARIANT PARK5 MET-93, CHARACTERIZATION OF VARIANT RP TYR-18, MUTAGENESIS OF CYS-90, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL RP PROPERTIES. RX PubMed=12705903; DOI=10.1016/s0006-291x(03)00555-2; RA Nishikawa K., Li H., Kawamura R., Osaka H., Wang Y.-L., Hara Y., RA Hirokawa T., Manago Y., Amano T., Noda M., Aoki S., Wada K.; RT "Alterations of structure and hydrolase activity of parkinsonism-associated RT human ubiquitin carboxyl-terminal hydrolase L1 variants."; RL Biochem. Biophys. Res. Commun. 304:176-183(2003). RN [26] RP VARIANT MET-93. RX PubMed=10454131; DOI=10.1016/s0304-3940(99)00465-6; RA Harhangi B.S., Farrer M.J., Lincoln S., Bonifati V., Meco G., RA De Michele G., Brice A., Durr A., Martinez M., Gasser T., Bereznai B., RA Vaughan J.R., Wood N.W., Hardy J., Oostra B.A., Breteler M.M.; RT "The Ile93Met mutation in the ubiquitin carboxy-terminal-hydrolase-L1 gene RT is not observed in European cases with familial Parkinson's disease."; RL Neurosci. Lett. 270:1-4(1999). RN [27] RP VARIANT TYR-18. RX PubMed=10203348; DOI=10.1097/00001756-199902050-00040; RA Lincoln S., Vaughan J., Wood N., Baker M., Adamson J., Gwinn-Hardy K., RA Lynch T., Hardy J., Farrer M.; RT "Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal RT hydrolase gene in familial Parkinson's disease."; RL NeuroReport 10:427-429(1999). RN [28] RP VARIANT TYR-18. RX PubMed=11027850; DOI=10.1016/s0304-3940(00)01510-x; RA Mellick G.D., Silburn P.A.; RT "The ubiquitin carboxy-terminal hydrolase-L1 gene S18Y polymorphism does RT not confer protection against idiopathic Parkinson's disease."; RL Neurosci. Lett. 293:127-130(2000). RN [29] RP VARIANT TYR-18. RX PubMed=15048890; DOI=10.1002/ana.20017; RG UCHL1 global genetics consortium; RA Maraganore D.M., Lesnick T.G., Elbaz A., Chartier-Harlin M.-C., Gasser T., RA Krueger R., Hattori N., Mellick G.D., Quattrone A., Satoh J., Toda T., RA Wang J., Ioannidis J.P.A., de Andrade M., Rocca W.A.; RT "UCHL1 is a Parkinson's disease susceptibility gene."; RL Ann. Neurol. 55:512-521(2004). RN [30] RP ERRATUM OF PUBMED:15048890. RG UCHL1 global genetics consortium; RA Maraganore D.M., Lesnick T.G., Elbaz A., Chartier-Harlin M.-C., Gasser T., RA Krueger R., Hattori N., Mellick G.D., Quattrone A., Satoh J., Toda T., RA Wang J., Ioannidis J.P.A., de Andrade M., Rocca W.A.; RL Ann. Neurol. 55:899-899(2004). RN [31] RP VARIANT TYR-18, AND LACK OF ASSOCIATION OF VARIANT TYR-18 WITH PARKINSON RP DISEASE. RX PubMed=16450370; DOI=10.1002/ana.20757; RA Healy D.G., Abou-Sleiman P.M., Casas J.P., Ahmadi K.R., Lynch T., RA Gandhi S., Muqit M.M., Foltynie T., Barker R., Bhatia K.P., Quinn N.P., RA Lees A.J., Gibson J.M., Holton J.L., Revesz T., Goldstein D.B., Wood N.W.; RT "UCHL-1 is not a Parkinson's disease susceptibility gene."; RL Ann. Neurol. 59:627-633(2006). RN [32] RP CHARACTERIZATION OF VARIANT TYR-18, AND ANTIOXIDANT FUNCTION IN NEURONAL RP CELLS. RX PubMed=18411255; DOI=10.1093/hmg/ddn115; RA Kyratzi E., Pavlaki M., Stefanis L.; RT "The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to RT neuronal cells."; RL Hum. Mol. Genet. 17:2160-2171(2008). RN [33] RP VARIANT TYR-18. RX PubMed=21268678; DOI=10.3109/13816810.2010.544360; RA Rudolph T., Sjolander A., Palmer M.S., Minthon L., Wallin A., Andreasen N., RA Tasa G., Juronen E., Blennow K., Zetterberg H., Zetterberg M.; RT "Ubiquitin carboxyl-terminal esterase L1 (UCHL1) S18Y polymorphism in RT patients with cataracts."; RL Ophthalmic Genet. 32:75-79(2011). RN [34] RP VARIANTS SPG79B GLN-178 AND ASP-216, AND CHARACTERIZATION OF VARIANTS RP SPG79B GLN-178 AND ASP-216. RX PubMed=28007905; DOI=10.1093/hmg/ddw391; RA Rydning S.L., Backe P.H., Sousa M.M., Iqbal Z., Oeye A.M., Sheng Y., RA Yang M., Lin X., Slupphaug G., Nordenmark T.H., Vigeland M.D., Bjoeraas M., RA Tallaksen C.M., Selmer K.K.; RT "Novel UCHL1 mutations reveal new insights into ubiquitin processing."; RL Hum. Mol. Genet. 26:1031-1040(2017). RN [35] RP VARIANTS SPG79A 2-GLN--ALA-223 DEL; 25-GLN--ALA-223 DEL; LEU-52 INS; RP 178-ARG--ALA-223 DEL AND 211-GLU--ALA-223 DEL, AND INVOLVEMENT IN SPG79A. RX PubMed=35986737; DOI=10.1016/j.gim.2022.07.006; RG Genomics England Research Consortium; RA Park J., Tucci A., Cipriani V., Demidov G., Rocca C., Senderek J., RA Butryn M., Velic A., Lam T., Galanaki E., Cali E., Vestito L., RA Maroofian R., Deininger N., Rautenberg M., Admard J., Hahn G.A., RA Bartels C., van Os N.J.H., Horvath R., Chinnery P.F., Tiet M.Y., RA Hewamadduma C., Hadjivassiliou M., Tofaris G.K., Wood N.W., Hayer S.N., RA Bender F., Menden B., Cordts I., Klein K., Nguyen H.P., Krauss J.K., RA Blahak C., Strom T.M., Sturm M., van de Warrenburg B., Lerche H., Macek B., RA Synofzik M., Ossowski S., Timmann D., Wolf M.E., Smedley D., Riess O., RA Schoels L., Houlden H., Haack T.B., Hengel H.; RT "Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative RT disorder with spasticity, ataxia, neuropathy, and optic atrophy."; RL Genet. Med. 24:2079-2090(2022). CC -!- FUNCTION: Deubiquitinase that plays a role in the regulation of several CC processes such as maintenance of synaptic function, cardiac function, CC inflammatory response or osteoclastogenesis (PubMed:22212137, CC PubMed:23359680). Abrogates the ubiquitination of multiple proteins CC including WWTR1/TAZ, EGFR, HIF1A and beta-site amyloid precursor CC protein cleaving enzyme 1/BACE1 (PubMed:22212137, PubMed:25615526). In CC addition, recognizes and hydrolyzes a peptide bond at the C-terminal CC glycine of ubiquitin to maintain a stable pool of monoubiquitin that is CC a key requirement for the ubiquitin-proteasome and the autophagy- CC lysosome pathways (PubMed:12408865, PubMed:8639624, PubMed:9774100). CC Regulates amyloid precursor protein/APP processing by promoting BACE1 CC degradation resulting in decreased amyloid beta production CC (PubMed:22212137). Plays a role in the immune response by regulating CC the ability of MHC I molecules to reach cross-presentation compartments CC competent for generating Ag-MHC I complexes (By similarity). Mediates CC the 'Lys-48'-linked deubiquitination of the transcriptional coactivator CC WWTR1/TAZ leading to its stabilization and inhibition of CC osteoclastogenesis (By similarity). Deubiquitinates and stabilizes CC epidermal growth factor receptor EGFR to prevent its degradation and to CC activate its downstream mediators (By similarity). Modulates oxidative CC activity in skeletal muscle by regulating key mitochondrial oxidative CC proteins (By similarity). Enhances the activity of hypoxia-inducible CC factor 1-alpha/HIF1A by abrogateing its VHL E3 ligase-mediated CC ubiquitination and consequently inhibiting its degradation CC (PubMed:25615526). {ECO:0000250|UniProtKB:Q9R0P9, CC ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:22212137, CC ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:25615526, CC ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide CC and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76- CC residue protein attached to proteins as an intracellular targeting CC signal).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:12408865, CC ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:16475834, CC ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680, CC ECO:0000269|PubMed:25615526, ECO:0000269|PubMed:8639624, CC ECO:0000269|PubMed:9774100}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=122 nM for Ub-AMC {ECO:0000269|PubMed:12705903, CC ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}; CC KM=1.20 uM for ubiquitin ethyl ester {ECO:0000269|PubMed:12705903, CC ECO:0000269|PubMed:8639624, ECO:0000269|PubMed:9774100}; CC Vmax=0.47 umol/min/mg enzyme toward Ub-AMC CC {ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:8639624, CC ECO:0000269|PubMed:9774100}; CC Vmax=25 umol/min/mg enzyme toward ubiquitin ethyl ester CC {ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:8639624, CC ECO:0000269|PubMed:9774100}; CC -!- SUBUNIT: Monomer. Homodimer. Interacts with SNCA (By similarity). CC Interacts with COPS5. {ECO:0000250, ECO:0000269|PubMed:12082530, CC ECO:0000269|PubMed:16537382, ECO:0000269|PubMed:20439756}. CC -!- INTERACTION: CC P09936; P63010-2: AP2B1; NbExp=3; IntAct=EBI-714860, EBI-11529439; CC P09936; P05067: APP; NbExp=5; IntAct=EBI-714860, EBI-77613; CC P09936; P05067-2: APP; NbExp=3; IntAct=EBI-714860, EBI-17264467; CC P09936; Q8N6T3-3: ARFGAP1; NbExp=3; IntAct=EBI-714860, EBI-10694449; CC P09936; P18847: ATF3; NbExp=3; IntAct=EBI-714860, EBI-712767; CC P09936; Q9H1Y0: ATG5; NbExp=4; IntAct=EBI-714860, EBI-1047414; CC P09936; O15392: BIRC5; NbExp=3; IntAct=EBI-714860, EBI-518823; CC P09936; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-714860, EBI-2837444; CC P09936; P83916: CBX1; NbExp=4; IntAct=EBI-714860, EBI-78129; CC P09936; P11802: CDK4; NbExp=4; IntAct=EBI-714860, EBI-295644; CC P09936; Q00535: CDK5; NbExp=2; IntAct=EBI-714860, EBI-1041567; CC P09936; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-714860, EBI-350590; CC P09936; Q92905: COPS5; NbExp=3; IntAct=EBI-714860, EBI-594661; CC P09936; P00533: EGFR; NbExp=3; IntAct=EBI-714860, EBI-297353; CC P09936; O60739: EIF1B; NbExp=4; IntAct=EBI-714860, EBI-1043343; CC P09936; Q8TC29: ENKUR; NbExp=3; IntAct=EBI-714860, EBI-9246952; CC P09936; Q9UI08-2: EVL; NbExp=3; IntAct=EBI-714860, EBI-6448852; CC P09936; Q8WVV9-3: HNRNPLL; NbExp=3; IntAct=EBI-714860, EBI-25845242; CC P09936; Q14164: IKBKE; NbExp=4; IntAct=EBI-714860, EBI-307369; CC P09936; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-714860, EBI-21911304; CC P09936; Q96JM7-2: L3MBTL3; NbExp=3; IntAct=EBI-714860, EBI-11985629; CC P09936; P13473-2: LAMP2; NbExp=3; IntAct=EBI-714860, EBI-21591415; CC P09936; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-714860, EBI-1108377; CC P09936; O95777: LSM8; NbExp=3; IntAct=EBI-714860, EBI-347779; CC P09936; A4FUJ8: MKL1; NbExp=3; IntAct=EBI-714860, EBI-21250407; CC P09936; Q15843: NEDD8; NbExp=4; IntAct=EBI-714860, EBI-716247; CC P09936; O15381-5: NVL; NbExp=3; IntAct=EBI-714860, EBI-18577082; CC P09936; Q9BR81: PCDHGC3; NbExp=3; IntAct=EBI-714860, EBI-22012354; CC P09936; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-714860, EBI-716063; CC P09936; P62826: RAN; NbExp=3; IntAct=EBI-714860, EBI-286642; CC P09936; Q8TAI7: RHEBL1; NbExp=3; IntAct=EBI-714860, EBI-746555; CC P09936; Q9ULX5: RNF112; NbExp=3; IntAct=EBI-714860, EBI-25829984; CC P09936; Q15554-4: TERF2; NbExp=3; IntAct=EBI-714860, EBI-25840535; CC P09936; Q9NYB0: TERF2IP; NbExp=2; IntAct=EBI-714860, EBI-750109; CC P09936; P04637: TP53; NbExp=3; IntAct=EBI-714860, EBI-366083; CC P09936; Q9Y4K3: TRAF6; NbExp=4; IntAct=EBI-714860, EBI-359276; CC P09936; P19474: TRIM21; NbExp=3; IntAct=EBI-714860, EBI-81290; CC P09936; Q9BSL1: UBAC1; NbExp=3; IntAct=EBI-714860, EBI-749370; CC P09936; Q7KZS0: UBE2I; NbExp=3; IntAct=EBI-714860, EBI-10180829; CC P09936; P61086: UBE2K; NbExp=3; IntAct=EBI-714860, EBI-473850; CC P09936; Q9UK80: USP21; NbExp=4; IntAct=EBI-714860, EBI-373242; CC P09936; Q86WB0-2: ZC3HC1; NbExp=3; IntAct=EBI-714860, EBI-25894765; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19261853}. CC Endoplasmic reticulum membrane {ECO:0000269|PubMed:19261853}; Lipid- CC anchor {ECO:0000269|PubMed:19261853}. Note=About 30% of total UCHL1 is CC associated with membranes in brain. Localizes near and/or within CC mitochondria to potentially interact with mitochondrial proteins. CC {ECO:0000250|UniProtKB:Q9R0P9}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative initiation; Named isoforms=3; CC Name=1; CC IsoId=P09936-1; Sequence=Displayed; CC Name=2; CC IsoId=P09936-2; Sequence=VSP_062524; CC Name=3; CC IsoId=P09936-3; Sequence=VSP_062523; CC -!- TISSUE SPECIFICITY: Found in neuronal cell bodies and processes CC throughout the neocortex (at protein level). Expressed in neurons and CC cells of the diffuse neuroendocrine system and their tumors. Weakly CC expressed in ovary. Down-regulated in brains from Parkinson disease and CC Alzheimer disease patients. {ECO:0000269|PubMed:14722078, CC ECO:0000269|PubMed:9790970}. CC -!- PTM: O-glycosylated. {ECO:0000250}. CC -!- DISEASE: Parkinson disease 5 (PARK5) [MIM:613643]: A complex CC neurodegenerative disorder with manifestations ranging from typical CC Parkinson disease to dementia with Lewy bodies. Clinical features CC include parkinsonian symptoms (resting tremor, rigidity, postural CC instability and bradykinesia), dementia, diffuse Lewy body pathology, CC autonomic dysfunction, hallucinations and paranoia. CC {ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, CC ECO:0000269|PubMed:9774100}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- DISEASE: Spastic paraplegia 79A, autosomal dominant, with ataxia CC (SPG79A) [MIM:620221]: A form of spastic paraplegia, a CC neurodegenerative disorder characterized by a slow, gradual, CC progressive weakness and spasticity of the lower limbs. Rate of CC progression and the severity of symptoms are quite variable. Initial CC symptoms may include difficulty with balance, weakness and stiffness in CC the legs, muscle spasms, and dragging the toes when walking. In some CC forms of the disorder, bladder symptoms (such as incontinence) may CC appear, or the weakness and stiffness may spread to other parts of the CC body. SPG79A is a slowly progressive form characterized by late-onset CC spastic ataxia, neuropathy, and often optic atrophy. CC {ECO:0000269|PubMed:35986737}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Spastic paraplegia 79B, autosomal recessive (SPG79B) CC [MIM:615491]: A form of spastic paraplegia, a neurodegenerative CC disorder characterized by a slow, gradual, progressive weakness and CC spasticity of the lower limbs. Rate of progression and the severity of CC symptoms are quite variable. Initial symptoms may include difficulty CC with balance, weakness and stiffness in the legs, muscle spasms, and CC dragging the toes when walking. In some forms of the disorder, bladder CC symptoms (such as incontinence) may appear, or the weakness and CC stiffness may spread to other parts of the body. SPG79B is CC characterized by childhood onset blindness, cerebellar ataxia, CC nystagmus, dorsal column dysfunction, and spasticity with upper motor CC neuron dysfunction. {ECO:0000269|PubMed:23359680, CC ECO:0000269|PubMed:28007905}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: Oxidation of Met-1, Met-6, Met-12, Met-124 and Met-179 CC to methionine sulfoxide, and oxidation of Cys-220 to cysteine sulfonic CC acid have been observed in brains from Alzheimer disease (AD) and CC Parkinson disease (PD) patients. In AD, UCHL1 was found to be CC associated with neurofibrillary tangles. In contrast to UCHL3, does not CC hydrolyze a peptide bond at the C-terminal glycine of NEDD8. CC -!- SIMILARITY: Belongs to the peptidase C12 family. {ECO:0000305}. CC -!- CAUTION: PubMed:9774100 reports the association of mutation Ile93Met CC with Parkinson disease. However, according to PubMed:16450370 this CC association is uncertain and UCHL1 is not a susceptibility gene for CC Parkinson disease. {ECO:0000305}. CC -!- CAUTION: The oxidation forms of Met-1, Met-6, Met-12, Met-124, Met-179 CC and Cys-220 are subject of controversy and could be the artifactual CC results of sample handling. {ECO:0000305|PubMed:14722078}. CC -!- CAUTION: The homodimer may have ATP-independent ubiquitin ligase CC activity (PubMed:12408865). However, in another study, UCHL1 was shown CC to lack ubiquitin ligase activity (PubMed:23359680). CC {ECO:0000269|PubMed:23359680, ECO:0000305|PubMed:12408865}. CC -!- SEQUENCE CAUTION: CC Sequence=CAA28443.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Wikipedia; Note=Ubiquitin carboxy-terminal hydrolase CC L1 entry; CC URL="https://en.wikipedia.org/wiki/Ubiquitin_carboxy-terminal_hydrolase_L1"; 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; AC095043; AAY40923.1; -; Genomic_DNA. DR EMBL; CH471069; EAW92983.1; -; Genomic_DNA. DR EMBL; BC000332; AAH00332.1; -; mRNA. DR EMBL; BC005117; AAH05117.1; -; mRNA. DR EMBL; BC006305; AAH06305.1; -; mRNA. DR EMBL; X17377; CAA35249.1; -; Genomic_DNA. DR EMBL; X04741; CAA28443.1; ALT_INIT; mRNA. DR EMBL; AH007277; AAD09172.1; -; Genomic_DNA. DR CCDS; CCDS3462.1; -. [P09936-1] DR PIR; A25856; A25856. DR RefSeq; NP_004172.2; NM_004181.4. [P09936-1] DR PDB; 2ETL; X-ray; 2.40 A; A/B=1-223. DR PDB; 2LEN; NMR; -; A=1-223. DR PDB; 3IFW; X-ray; 2.40 A; A=1-223. DR PDB; 3IRT; X-ray; 2.80 A; A/B=1-223. DR PDB; 3KVF; X-ray; 2.80 A; A=1-223. DR PDB; 3KW5; X-ray; 2.83 A; A=1-223. DR PDB; 4DM9; X-ray; 2.35 A; A/B=1-223. DR PDB; 4JKJ; X-ray; 2.15 A; A/B=1-223. DR PDB; 7ZM0; X-ray; 2.24 A; A/B/C/D/E/F/G/H/I/J=1-223. DR PDB; 8DY8; X-ray; 2.10 A; A/B=1-223. DR PDB; 8EDE; X-ray; 1.80 A; A/B=1-223. DR PDB; 8PW1; X-ray; 2.20 A; A/B/C/D/E/F/G/H/I/J=1-223. DR PDB; 8XI7; X-ray; 1.95 A; A/B=1-223. DR PDB; 9O4M; X-ray; 2.00 A; A/B=1-223. DR PDBsum; 2ETL; -. DR PDBsum; 2LEN; -. DR PDBsum; 3IFW; -. DR PDBsum; 3IRT; -. DR PDBsum; 3KVF; -. DR PDBsum; 3KW5; -. DR PDBsum; 4DM9; -. DR PDBsum; 4JKJ; -. DR PDBsum; 7ZM0; -. DR PDBsum; 8DY8; -. DR PDBsum; 8EDE; -. DR PDBsum; 8PW1; -. DR PDBsum; 8XI7; -. DR PDBsum; 9O4M; -. DR AlphaFoldDB; P09936; -. DR BMRB; P09936; -. DR SASBDB; P09936; -. DR SMR; P09936; -. DR BioGRID; 113192; 258. DR CORUM; P09936; -. DR DIP; DIP-36620N; -. DR FunCoup; P09936; 1475. DR IntAct; P09936; 199. DR MINT; P09936; -. DR STRING; 9606.ENSP00000284440; -. DR BindingDB; P09936; -. DR ChEMBL; CHEMBL6159; -. DR DrugBank; DB12695; Phenethyl Isothiocyanate. DR GuidetoPHARMACOLOGY; 2426; -. DR MEROPS; C12.001; -. DR GlyGen; P09936; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P09936; -. DR MetOSite; P09936; -. DR PhosphoSitePlus; P09936; -. DR SwissPalm; P09936; -. DR BioMuta; UCHL1; -. DR DMDM; 136681; -. DR CPTAC; CPTAC-601; -. DR CPTAC; CPTAC-602; -. DR jPOST; P09936; -. DR MassIVE; P09936; -. DR PaxDb; 9606-ENSP00000284440; -. DR PeptideAtlas; P09936; -. DR ProteomicsDB; 52282; -. DR Pumba; P09936; -. DR Antibodypedia; 1062; 2368 antibodies from 53 providers. DR DNASU; 7345; -. DR Ensembl; ENST00000284440.9; ENSP00000284440.4; ENSG00000154277.14. [P09936-1] DR Ensembl; ENST00000503431.5; ENSP00000422542.1; ENSG00000154277.14. [P09936-1] DR GeneID; 7345; -. DR KEGG; hsa:7345; -. DR MANE-Select; ENST00000284440.9; ENSP00000284440.4; NM_004181.5; NP_004172.2. DR AGR; HGNC:12513; -. DR ClinPGx; PA37160; -. DR CTD; 7345; -. DR DisGeNET; 7345; -. DR GeneCards; UCHL1; -. DR HGNC; HGNC:12513; UCHL1. DR HPA; ENSG00000154277; Group enriched (brain, pituitary gland). DR MalaCards; UCHL1; -. DR MIM; 191342; gene. DR MIM; 613643; phenotype. DR MIM; 615491; phenotype. DR MIM; 620221; phenotype. DR OpenTargets; ENSG00000154277; -. DR Orphanet; 352654; Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome. DR Orphanet; 2828; Young-onset Parkinson disease. DR VEuPathDB; HostDB:ENSG00000154277; -. DR eggNOG; KOG1415; Eukaryota. DR GeneTree; ENSGT00940000157306; -. DR HOGENOM; CLU_054406_2_0_1; -. DR InParanoid; P09936; -. DR OMA; AQTYSKH; -. DR OrthoDB; 427186at2759; -. DR PAN-GO; P09936; 3 GO annotations based on evolutionary models. DR PhylomeDB; P09936; -. DR BRENDA; 3.4.19.12; 2681. DR PathwayCommons; P09936; -. DR Reactome; R-HSA-5689603; UCH proteinases. DR SABIO-RK; P09936; -. DR SignaLink; P09936; -. DR SIGNOR; P09936; -. DR Agora; ENSG00000154277; -. DR BioGRID-ORCS; 7345; 9 hits in 1196 CRISPR screens. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; UCHL1; human. DR EvolutionaryTrace; P09936; -. DR GeneWiki; Ubiquitin_carboxy-terminal_hydrolase_L1; -. DR GenomeRNAi; 7345; -. DR Pharos; P09936; Tchem. DR PRO; PR:P09936; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; P09936; protein. DR Bgee; ENSG00000154277; Expressed in pons and 169 other cell types or tissues. DR ExpressionAtlas; P09936; baseline and differential. DR GO; GO:1904115; C:axon cytoplasm; IEA:GOC. DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0044306; C:neuron projection terminus; IEA:Ensembl. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0031694; F:alpha-2A adrenergic receptor binding; IPI:BHF-UCL. DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB. DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IDA:UniProtKB. DR GO; GO:0008242; F:omega peptidase activity; IDA:UniProtKB. DR GO; GO:0043022; F:ribosome binding; IEA:Ensembl. DR GO; GO:0030547; F:signaling receptor inhibitor activity; IDA:BHF-UCL. DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0007628; P:adult walking behavior; IEA:Ensembl. DR GO; GO:0007412; P:axon target recognition; IEA:Ensembl. DR GO; GO:0019896; P:axonal transport of mitochondrion; IEA:Ensembl. DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0042755; P:eating behavior; IEA:Ensembl. DR GO; GO:0002176; P:male germ cell proliferation; IEA:Ensembl. DR GO; GO:0055001; P:muscle cell development; IEA:Ensembl. DR GO; GO:0043409; P:negative regulation of MAPK cascade; IDA:BHF-UCL. DR GO; GO:0050905; P:neuromuscular process; IEA:Ensembl. DR GO; GO:0045821; P:positive regulation of glycolytic process; IMP:FlyBase. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; NAS:ParkinsonsUK-UCL. DR GO; GO:0030163; P:protein catabolic process; IBA:GO_Central. DR GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB. DR GO; GO:0016241; P:regulation of macroautophagy; TAS:ParkinsonsUK-UCL. DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl. DR CDD; cd09616; Peptidase_C12_UCH_L1_L3; 1. DR FunFam; 3.40.532.10:FF:000004; Ubiquitin carboxyl-terminal hydrolase; 1. DR Gene3D; 3.40.532.10; Peptidase C12, ubiquitin carboxyl-terminal hydrolase; 1. DR InterPro; IPR038765; Papain-like_cys_pep_sf. DR InterPro; IPR001578; Peptidase_C12_UCH. DR InterPro; IPR036959; Peptidase_C12_UCH_sf. DR InterPro; IPR057254; UCH_AS. DR PANTHER; PTHR10589; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE; 1. DR PANTHER; PTHR10589:SF19; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE ISOZYME L1; 1. DR Pfam; PF01088; Peptidase_C12; 1. DR PRINTS; PR00707; UBCTHYDRLASE. DR SUPFAM; SSF54001; Cysteine proteinases; 1. DR PROSITE; PS00140; UCH_1; 1. DR PROSITE; PS52048; UCH_DOMAIN; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative initiation; Cytoplasm; KW Direct protein sequencing; Disease variant; Endoplasmic reticulum; KW Glycoprotein; Hereditary spastic paraplegia; Hydrolase; Lipoprotein; KW Membrane; Neurodegeneration; Oxidation; Parkinson disease; Parkinsonism; KW Phosphoprotein; Prenylation; Protease; Proteomics identification; KW Reference proteome; Thiol protease; Ubl conjugation pathway. FT CHAIN 1..220 FT /note="Ubiquitin carboxyl-terminal hydrolase isozyme L1" FT /id="PRO_0000211055" FT PROPEP 221..223 FT /note="Removed in mature form" FT /evidence="ECO:0000305" FT /id="PRO_0000414311" FT DOMAIN 2..221 FT /note="UCH catalytic" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393" FT REGION 5..10 FT /note="Interaction with ubiquitin" FT /evidence="ECO:0000269|PubMed:20439756" FT REGION 211..216 FT /note="Interaction with ubiquitin" FT /evidence="ECO:0000269|PubMed:20439756" FT ACT_SITE 90 FT /note="Nucleophile" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393, FT ECO:0000269|PubMed:20439756" FT ACT_SITE 161 FT /note="Proton donor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393, FT ECO:0000269|PubMed:20439756" FT SITE 1 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 6 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 12 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 84 FT /note="Transition state stabilizer" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393, FT ECO:0000269|PubMed:8639624" FT SITE 124 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 176 FT /note="Important for enzyme activity" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01393" FT SITE 179 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT SITE 220 FT /note="Susceptible to oxidation" FT /evidence="ECO:0000269|PubMed:14722078" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|PubMed:37316325" FT MOD_RES 125 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q00981" FT LIPID 220 FT /note="S-farnesyl cysteine" FT /evidence="ECO:0000269|PubMed:19261853" FT VAR_SEQ 1..11 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000269|PubMed:37316325" FT /id="VSP_062523" FT VAR_SEQ 1..5 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000269|PubMed:37316325" FT /id="VSP_062524" FT VARIANT 2..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087898" FT VARIANT 7 FT /note="E -> A (in SPG79B; has decreased binding to FT ubiquitin and significantly decreased hydrolase activity FT compared to wild-type; dbSNP:rs397515634)" FT /evidence="ECO:0000269|PubMed:23359680" FT /id="VAR_070875" FT VARIANT 18 FT /note="S -> Y (it confers protection from oxidative stress FT when expressed at physiological levels in neuroblastoma FT cells and primary cortical neurons; loss of dimerization FT ability; impaired ligase activity; dbSNP:rs5030732)" FT /evidence="ECO:0000269|PubMed:10203348, FT ECO:0000269|PubMed:11027850, ECO:0000269|PubMed:12408865, FT ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:15048890, FT ECO:0000269|PubMed:16450370, ECO:0000269|PubMed:18411255, FT ECO:0000269|PubMed:21268678" FT /id="VAR_015677" FT VARIANT 25..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087899" FT VARIANT 52 FT /note="L -> LL (in SPG79A; uncertain significance)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087900" FT VARIANT 93 FT /note="I -> M (in PARK5; impaired enzymatic hydrolase FT activity; has about a 50% reduction in catalytic activity FT compared to wild-type protein; dbSNP:rs121917767)" FT /evidence="ECO:0000269|PubMed:10454131, FT ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, FT ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:9774100" FT /id="VAR_015678" FT VARIANT 178..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087901" FT VARIANT 178 FT /note="R -> Q (in SPG79B; increased hydrolase activity; FT decreased protein abundance; dbSNP:rs768996179)" FT /evidence="ECO:0000269|PubMed:28007905" FT /id="VAR_078119" FT VARIANT 211..223 FT /note="Missing (in SPG79A)" FT /evidence="ECO:0000269|PubMed:35986737" FT /id="VAR_087902" FT VARIANT 216 FT /note="A -> D (in SPG79B; decreased protein abundance; FT dbSNP:rs1057519600)" FT /evidence="ECO:0000269|PubMed:28007905" FT /id="VAR_078120" FT MUTAGEN 73 FT /note="Q->R: No effect on enzymatic parameters." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 90 FT /note="C->S: Abolishes enzymatic activity." FT /evidence="ECO:0000269|PubMed:12705903, FT ECO:0000269|PubMed:20439756, ECO:0000269|PubMed:23359680, FT ECO:0000269|PubMed:25615526, ECO:0000269|PubMed:8639624" FT MUTAGEN 97 FT /note="H->Q,N: 2-fold increase in affinity for ubiquitin FT ethyl ester, slight reduction in enzymatic activity." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 161 FT /note="H->D: 10000-fold decrease in enzymatic activity; no FT change in affinity for ubiquitin ethyl ester." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 161 FT /note="H->K,Q,N,Y: Abolishes enzymatic activity." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 176 FT /note="D->N: 6-fold decrease in affinity for ubiquitin FT ethyl ester; 97.5% decrease in enzymatic activity." FT /evidence="ECO:0000269|PubMed:8639624" FT MUTAGEN 204 FT /note="F->A: Almost complete loss of activity." FT /evidence="ECO:0000269|PubMed:20439756" FT HELIX 10..19 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 22..25 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 27..31 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 36..41 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 46..54 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 57..70 FT /evidence="ECO:0007829|PDB:8EDE" FT TURN 71..74 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 86..88 FT /evidence="ECO:0007829|PDB:2LEN" FT HELIX 90..100 FT /evidence="ECO:0007829|PDB:8EDE" FT TURN 101..105 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 113..120 FT /evidence="ECO:0007829|PDB:8EDE" FT TURN 121..123 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 126..135 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 137..147 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 160..168 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 171..175 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 179..181 FT /evidence="ECO:0007829|PDB:8EDE" FT STRAND 183..187 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 190..192 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 193..207 FT /evidence="ECO:0007829|PDB:8EDE" FT HELIX 211..213 FT /evidence="ECO:0007829|PDB:2LEN" FT STRAND 215..220 FT /evidence="ECO:0007829|PDB:8EDE" FT MOD_RES P09936-2:1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|PubMed:37316325" FT MOD_RES P09936-3:1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000269|PubMed:37316325" SQ SEQUENCE 223 AA; 24824 MW; C9E972AC4DA5DA8A CRC64; MQLKPMEINP EMLNKVLSRL GVAGQWRFVD VLGLEEESLG SVPAPACALL LLFPLTAQHE NFRKKQIEEL KGQEVSPKVY FMKQTIGNSC GTIGLIHAVA NNQDKLGFED GSVLKQFLSE TEKMSPEDRA KCFEKNEAIQ AAHDAVAQEG QCRVDDKVNF HFILFNNVDG HLYELDGRMP FPVNHGASSE DTLLKDAAKV CREFTEREQG EVRFSAVALC KAA //