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 02-SEP-2026, entry version 245. 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; 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; 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; Q9BSL1: UBAC1; NbExp=3; IntAct=EBI-2010251, EBI-749370; 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: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 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; 74. DR MINT; P49810; -. DR NDEx; IQUERY-CP-PSEN2; 11 NDEx IQuery Curated Pathways. 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; 470 antibodies from 44 providers. DR DNASU; 5664; -. DR Ensembl; ENST00000366779.6; ENSP00000355741.2; ENSG00000288674.1. [P49810-1] 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; ENST00000676884.1; ENSP00000503200.1; ENSG00000288674.1. [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 Ensembl; ENST00000900065.1; ENSP00000570124.1; ENSG00000143801.19. [P49810-3] DR Ensembl; ENST00000900066.1; ENSP00000570125.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000900067.1; ENSP00000570126.1; ENSG00000143801.19. [P49810-3] DR Ensembl; ENST00000900068.1; ENSP00000570127.1; ENSG00000143801.19. [P49810-3] DR Ensembl; ENST00000900069.1; ENSP00000570128.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000900071.1; ENSP00000570130.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000900072.1; ENSP00000570131.1; ENSG00000143801.19. [P49810-3] DR Ensembl; ENST00000900073.1; ENSP00000570132.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000900074.1; ENSP00000570133.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000900075.1; ENSP00000570134.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000900077.1; ENSP00000570136.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000940855.1; ENSP00000610914.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000940856.1; ENSP00000610915.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000940857.1; ENSP00000610916.1; ENSG00000143801.19. [P49810-3] DR Ensembl; ENST00000940858.1; ENSP00000610917.1; ENSG00000143801.19. [P49810-3] DR Ensembl; ENST00000940859.1; ENSP00000610918.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000940860.1; ENSP00000610919.1; ENSG00000143801.19. [P49810-3] DR Ensembl; ENST00000940862.1; ENSP00000610921.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000940863.1; ENSP00000610922.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000940864.1; ENSP00000610923.1; ENSG00000143801.19. [P49810-3] DR Ensembl; ENST00000968761.1; ENSP00000638820.1; ENSG00000143801.19. [P49810-3] DR Ensembl; ENST00000968763.1; ENSP00000638822.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000968764.1; ENSP00000638823.1; ENSG00000143801.19. [P49810-3] DR Ensembl; ENST00000968765.1; ENSP00000638824.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000968766.1; ENSP00000638825.1; ENSG00000143801.19. [P49810-3] DR Ensembl; ENST00000968768.1; ENSP00000638827.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000968769.1; ENSP00000638828.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000968770.1; ENSP00000638829.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000968772.1; ENSP00000638831.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000968773.1; ENSP00000638832.1; ENSG00000143801.19. [P49810-1] DR Ensembl; ENST00000968774.1; ENSP00000638833.1; ENSG00000143801.19. [P49810-3] DR Ensembl; ENST00000968775.1; ENSP00000638834.1; ENSG00000143801.19. [P49810-3] DR Ensembl; ENST00000968776.1; ENSP00000638835.1; ENSG00000143801.19. [P49810-3] DR Ensembl; ENST00000968777.1; ENSP00000638836.1; ENSG00000143801.19. [P49810-3] DR Ensembl; ENST00000968778.1; ENSP00000638837.1; ENSG00000143801.19. [P49810-3] DR Ensembl; ENST00000968779.1; ENSP00000638838.1; 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; 7 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; EXP:UniProtKB. DR GO; GO:0070765; C:gamma-secretase complex; IDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; IDA:HGNC-UCL. DR GO; GO:0000139; C:Golgi membrane; EXP:UniProtKB. DR GO; GO:0000776; C:kinetochore; IDA:UniProtKB. DR GO; GO:0005770; C:late endosome; IDA:UniProtKB. DR GO; GO:0031902; C:late endosome membrane; EXP:UniProtKB. DR GO; GO:0005765; C:lysosomal membrane; EXP:UniProtKB. DR GO; GO:0005764; C:lysosome; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0044233; C:mitochondria-associated endoplasmic reticulum membrane contact site; ISS: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; IDA:UniProtKB. DR GO; GO:0042987; P:amyloid precursor protein catabolic process; IDA:ARUK-UCL. DR GO; GO:0034205; P:amyloid-beta formation; IDA:UniProtKB. 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:0035333; P:Notch receptor processing, ligand-dependent; IDA:UniProtKB. 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. DR PDBsum; 7Y5X; -. DR PDBsum; 7Y5Z; -. 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; does 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 //