PSN2_HUMAN
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 03-AUG-2022, entry version 226.
DE RecName: Full=Presenilin-2;
DE Short=PS-2;
DE EC=3.4.23.-;
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;
DE Contains:
DE RecName: Full=Presenilin-2 CTF subunit;
GN Name=PSEN2; Synonyms=AD4, PS2, PSNL2, STM2;
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 [MRNA].
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 [4]
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 [5]
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 [6]
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 [7]
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 [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].
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 [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, ACTIVE SITE ASP-366, AND MUTAGENESIS OF 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, ACTIVE SITES ASP-263 AND ASP-366, AND MUTAGENESIS OF ASP-263 AND
RP 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 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 [16]
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 [17]
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 [18]
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 [19]
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 [20]
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 [21]
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 [22]
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 [23]
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 [24]
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 [25]
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 [26]
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 [27]
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 [28]
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 [29]
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 [30]
RP 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 [31]
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 [32]
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 [33]
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 [34]
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: Probable 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). Requires the other members of the gamma-
CC secretase complex to have a protease activity. May play a role in
CC intracellular signaling and gene expression or in linking chromatin to
CC the nuclear membrane. May function in the cytoplasmic partitioning of
CC proteins. The holoprotein functions as a calcium-leak channel that
CC allows the passive movement of calcium from endoplasmic reticulum to
CC cytosol and is involved in calcium homeostasis (PubMed:16959576). Is a
CC regulator of mitochondrion-endoplasmic reticulum membrane tethering and
CC modulates calcium ions shuttling between ER and mitochondria
CC (PubMed:21285369). {ECO:0000269|PubMed:10497236,
CC ECO:0000269|PubMed:10652302, ECO:0000269|PubMed:16959576,
CC ECO:0000269|PubMed:21285369}.
CC -!- SUBUNIT: Interacts with DOCK3 (By similarity). Homodimer. Component of
CC the gamma-secretase complex, a complex composed of a presenilin
CC homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B)
CC and PEN2. Such minimal complex is sufficient for secretase activity,
CC although other components may exist. Interacts with HERPUD1, FLNA, FLNB
CC and PARL. {ECO:0000250, ECO:0000269|PubMed:11799129,
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; P29466-3: CASP1; NbExp=3; IntAct=EBI-2010251, EBI-12248206;
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; 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; 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; Q9BSL1: UBAC1; NbExp=3; IntAct=EBI-2010251, EBI-749370;
CC P49810; Q9GZS3: WDR61; NbExp=3; IntAct=EBI-2010251, EBI-358545;
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 -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:8574969}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:8574969}. Golgi apparatus membrane
CC {ECO:0000269|PubMed:8574969}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:8574969}.
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 is seen in the placenta, skeletal muscle
CC and heart while isoform 2 is seen in the heart, brain, placenta, liver,
CC skeletal muscle and kidney. {ECO:0000269|PubMed:8574969}.
CC -!- DOMAIN: The PAL motif is required for normal active site conformation.
CC {ECO:0000250}.
CC -!- PTM: Heterogeneous proteolytic processing generates N-terminal and C-
CC terminal fragments.
CC -!- PTM: Phosphorylated on serine residues.
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:7638622, ECO:0000269|PubMed:7651536,
CC ECO:0000269|PubMed:9384602}. Note=The disease is caused by variants
CC affecting the gene represented in this 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 -!- WEB RESOURCE: Name=Alzheimer Research Forum; Note=Presenilins
CC mutations;
CC URL="https://www.alzforum.org/mutations/search?genes%255B%255D=348";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/PSEN2ID41883ch1q42.html";
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DR EMBL; L43964; AAB59557.1; -; mRNA.
DR EMBL; L44577; AAC42012.1; -; mRNA.
DR EMBL; U34349; AAC50290.1; -; 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; 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_000447.2. [P49810-1]
DR RefSeq; NP_036618.2; NM_012486.2. [P49810-3]
DR RefSeq; XP_005273256.1; XM_005273199.3. [P49810-1]
DR RefSeq; XP_016857324.1; XM_017001835.1. [P49810-1]
DR RefSeq; XP_016857325.1; XM_017001836.1. [P49810-3]
DR AlphaFoldDB; P49810; -.
DR PCDDB; P49810; -.
DR SMR; P49810; -.
DR BioGRID; 111643; 70.
DR ComplexPortal; CPX-4231; Gamma-secretase complex, APH1A-PSEN2 variant.
DR ComplexPortal; CPX-4232; Gamma-secretase complex, APH1B-PSEN2 variant.
DR CORUM; P49810; -.
DR IntAct; P49810; 61.
DR MINT; P49810; -.
DR STRING; 9606.ENSP00000355747; -.
DR BindingDB; P49810; -.
DR ChEMBL; CHEMBL3708; -.
DR MEROPS; A22.002; -.
DR TCDB; 1.A.54.1.2; the presenilin er ca(2+) leak channel (presenilin) family.
DR iPTMnet; P49810; -.
DR PhosphoSitePlus; P49810; -.
DR SwissPalm; P49810; -.
DR BioMuta; PSEN2; -.
DR DMDM; 1709858; -.
DR EPD; P49810; -.
DR jPOST; P49810; -.
DR MassIVE; P49810; -.
DR MaxQB; P49810; -.
DR PaxDb; P49810; -.
DR PeptideAtlas; P49810; -.
DR PRIDE; P49810; -.
DR ProteomicsDB; 56139; -. [P49810-1]
DR ProteomicsDB; 56140; -. [P49810-2]
DR ProteomicsDB; 56141; -. [P49810-3]
DR Antibodypedia; 4424; 444 antibodies from 40 providers.
DR DNASU; 5664; -.
DR Ensembl; ENST00000366782.6; ENSP00000355746.2; ENSG00000143801.18. [P49810-1]
DR Ensembl; ENST00000366783.8; ENSP00000355747.3; ENSG00000143801.18. [P49810-1]
DR Ensembl; ENST00000422240.6; ENSP00000403737.2; ENSG00000143801.18. [P49810-3]
DR Ensembl; ENST00000524196.6; ENSP00000429036.2; ENSG00000143801.18. [P49810-1]
DR Ensembl; ENST00000626989.3; ENSP00000486498.2; ENSG00000143801.18. [P49810-1]
DR Ensembl; ENST00000677414.1; ENSP00000503116.1; ENSG00000143801.18. [P49810-1]
DR Ensembl; ENST00000678233.1; ENSP00000504728.1; ENSG00000143801.18. [P49810-1]
DR Ensembl; ENST00000679088.1; ENSP00000504727.1; ENSG00000143801.18. [P49810-1]
DR Ensembl; ENST00000679098.1; ENSP00000504303.1; ENSG00000143801.18. [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 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 neXtProt; NX_P49810; -.
DR NIAGADS; ENSG00000143801; -.
DR OpenTargets; ENSG00000143801; -.
DR Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease.
DR Orphanet; 154; Familial isolated dilated cardiomyopathy.
DR PharmGKB; PA33856; -.
DR VEuPathDB; HostDB:ENSG00000143801; -.
DR eggNOG; KOG2736; Eukaryota.
DR GeneTree; ENSGT00940000157923; -.
DR HOGENOM; CLU_022975_3_1_1; -.
DR InParanoid; P49810; -.
DR OMA; GVLIWNF; -.
DR OrthoDB; 797738at2759; -.
DR PhylomeDB; P49810; -.
DR TreeFam; TF315040; -.
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 SignaLink; P49810; -.
DR SIGNOR; P49810; -.
DR BioGRID-ORCS; 5664; 9 hits in 1077 CRISPR screens.
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 97 other tissues.
DR ExpressionAtlas; P49810; baseline and differential.
DR Genevisible; P49810; HS.
DR GO; GO:0016324; C:apical plasma membrane; IBA:GO_Central.
DR GO; GO:0005938; C:cell cortex; IBA:GO_Central.
DR GO; GO:0009986; C:cell surface; IBA:GO_Central.
DR GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR GO; GO:0035253; C:ciliary rootlet; IBA:GO_Central.
DR GO; GO:0043198; C:dendritic shaft; IBA:GO_Central.
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; IC:ComplexPortal.
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; IC:ComplexPortal.
DR GO; GO:0030426; C:growth cone; IBA:GO_Central.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:HGNC-UCL.
DR GO; GO:0099056; C:integral component of presynaptic membrane; IEA:Ensembl.
DR GO; GO:0000776; C:kinetochore; IDA:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; IBA:GO_Central.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0045121; C:membrane raft; IBA:GO_Central.
DR GO; GO:0005743; C:mitochondrial inner membrane; IBA:GO_Central.
DR GO; GO:0031594; C:neuromuscular junction; IBA:GO_Central.
DR GO; GO:0043025; C:neuronal cell body; IBA:GO_Central.
DR GO; GO:0005637; C:nuclear inner membrane; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB.
DR GO; GO:0008021; C:synaptic vesicle; IEA:Ensembl.
DR GO; GO:0030018; C:Z disc; IBA:GO_Central.
DR GO; GO:0042500; F:aspartic endopeptidase activity, intramembrane cleaving; IEA:InterPro.
DR GO; GO:0004175; F:endopeptidase activity; 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:0050435; P:amyloid-beta metabolic process; IBA:GO_Central.
DR GO; GO:0006816; P:calcium ion transport; 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:0043066; P:negative regulation of apoptotic process; IBA:GO_Central.
DR GO; GO:0007220; P:Notch receptor processing; IBA:GO_Central.
DR GO; GO:0007219; P:Notch signaling pathway; IEA:UniProtKB-KW.
DR GO; GO:0043085; P:positive regulation of catalytic activity; IDA:HGNC-UCL.
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 Gene3D; 1.10.472.100; -; 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; PTHR10202; 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 Alternative splicing; Alzheimer disease; Amyloidosis; Cardiomyopathy;
KW Disease variant; Endoplasmic reticulum; Golgi apparatus; Hydrolase;
KW Membrane; Neurodegeneration; Notch signaling pathway; Phosphoprotein;
KW Protease; Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..297
FT /note="Presenilin-2 NTF subunit"
FT /evidence="ECO:0000250"
FT /id="PRO_0000025603"
FT CHAIN 298..448
FT /note="Presenilin-2 CTF subunit"
FT /evidence="ECO:0000250"
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 414..416
FT /note="PAL"
FT COMPBIAS 20..45
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 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 variant;
FT 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; unknown pathological 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; dbSNP:rs63749851)"
FT /evidence="ECO:0000269|PubMed:10631141"
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; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:24844686"
FT /id="VAR_081262"
FT VARIANT 130
FT /note="S -> L (in CMD1V and AD4; unknown pathological
FT significance; 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 dbSNP:rs63750215)"
FT /evidence="ECO:0000269|PubMed:16752394,
FT ECO:0000269|PubMed:16959576, ECO:0000269|PubMed:21285369,
FT ECO:0000269|PubMed:7638622, 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; dbSNP:rs63749884)"
FT /evidence="ECO:0000269|PubMed:10631141"
FT /id="VAR_009215"
FT VARIANT 239
FT /note="M -> V (in AD4; dbSNP:rs28936379)"
FT /evidence="ECO:0000269|PubMed:7651536"
FT /id="VAR_006463"
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 and 10)"
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. 3; AAC50290)"
FT /evidence="ECO:0000305"
FT CONFLICT 358
FT /note="R -> SQG (in Ref. 3; AAC50290)"
FT /evidence="ECO:0000305"
FT CONFLICT 432..448
FT /note="NLVRPFMDTLASHQLYI -> RKHSRFIQMN (in Ref. 3)"
FT /evidence="ECO:0000305"
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
