ID NICA_HUMAN Reviewed; 709 AA. AC Q92542; Q5T207; Q5T208; Q86VV5; DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot. DT 11-JAN-2001, sequence version 2. DT 27-MAR-2024, entry version 209. DE RecName: Full=Nicastrin; DE Flags: Precursor; GN Name=NCSTN; Synonyms=KIAA0253; ORFNames=UNQ1874/PRO4317; 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), IDENTIFICATION BY MASS RP SPECTROMETRY, FUNCTION, IDENTIFICATION IN THE GAMMA-SECRETASE COMPLEX, RP INTERACTION WITH PSEN1 AND PSEN2, SUBCELLULAR LOCATION, GLYCOSYLATION, RP TISSUE SPECIFICITY, AND MUTAGENESIS OF 336-ASP-TYR-337. RC TISSUE=Embryonic kidney; RX PubMed=10993067; DOI=10.1038/35024009; RA Yu G., Nishimura M., Arawaka S., Levitan D., Zhang L., Tandon A., RA Song Y.-Q., Rogaeva E., Chen F., Kawarai T., Supala A., Levesque L., Yu H., RA Yang D.-S., Holmes E., Milman P., Liang Y., Zhang D.M., Xu D.H., Sato C., RA Rogaev E., Smith M., Janus C., Zhang Y., Aebersold R., Farrer L.S., RA Sorbi S., Bruni A., Fraser P.E., St George-Hyslop P.H.; RT "Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction RT and betaAPP processing."; RL Nature 407:48-54(2000). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RX PubMed=12975309; DOI=10.1101/gr.1293003; RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A., RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.; RT "The secreted protein discovery initiative (SPDI), a large-scale effort to RT identify novel human secreted and transmembrane proteins: a bioinformatics RT assessment."; RL Genome Res. 13:2265-2270(2003). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). 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 [4] 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 [5] 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). 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 [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 2-709 (ISOFORM 1). RC TISSUE=Bone marrow; RX PubMed=9039502; DOI=10.1093/dnares/3.5.321; RA Nagase T., Seki N., Ishikawa K., Ohira M., Kawarabayasi Y., Ohara O., RA Tanaka A., Kotani H., Miyajima N., Nomura N.; RT "Prediction of the coding sequences of unidentified human genes. VI. The RT coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of RT cDNA clones from cell line KG-1 and brain."; RL DNA Res. 3:321-329(1996). RN [8] RP TISSUE SPECIFICITY, AND INDUCTION. RX PubMed=11396676; DOI=10.1046/j.1440-1789.2001.00378.x; RA Satoh J., Kuroda Y.; RT "Nicastrin, a key regulator of presenilin function, is expressed RT constitutively in human neural cell lines."; RL Neuropathology 21:115-122(2001). RN [9] RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS]. RC TISSUE=Melanoma; RX PubMed=12643545; DOI=10.1021/pr025562r; RA Basrur V., Yang F., Kushimoto T., Higashimoto Y., Yasumoto K., Valencia J., RA Muller J., Vieira W.D., Watabe H., Shabanowitz J., Hearing V.J., Hunt D.F., RA Appella E.; RT "Proteomic analysis of early melanosomes: identification of novel RT melanosomal proteins."; RL J. Proteome Res. 2:69-79(2003). RN [10] RP COMPONENT OF A GAMMA-SECRETASE COMPLEX WITH PEN2; PSEN1/PSEN2 AND APH1A. 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 [11] RP ENZYME ACTIVITY OF A GAMMA-SECRETASE COMPLEX. 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 [12] RP GLYCOSYLATION AT ASN-387. RX PubMed=12754519; DOI=10.1038/nbt827; RA Zhang H., Li X.-J., Martin D.B., Aebersold R.; RT "Identification and quantification of N-linked glycoproteins using RT hydrazide chemistry, stable isotope labeling and mass spectrometry."; RL Nat. Biotechnol. 21:660-666(2003). RN [13] RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS]. RC TISSUE=Melanoma; RX PubMed=17081065; DOI=10.1021/pr060363j; RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H., Mangini N.J., RA Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R., Yamagishi S., RA Shabanowitz J., Hearing V.J., Wu C., Appella E., Hunt D.F.; RT "Proteomic and bioinformatic characterization of the biogenesis and RT function of melanosomes."; RL J. Proteome Res. 5:3135-3144(2006). RN [14] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-45; ASN-187 AND ASN-387. 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-612. 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 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 [17] 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 [18] RP STRUCTURE BY ELECTRON MICROSCOPY (5.40 ANGSTROMS), FUNCTION, SUBCELLULAR RP LOCATION, TOPOLOGY, SUBUNIT, DISULFIDE BONDS, AND GLYCOSYLATION. 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 [19] RP STRUCTURE BY ELECTRON MICROSCOPY (4.00 ANGSTROMS), DISULFIDE BONDS, RP SUBCELLULAR LOCATION, TOPOLOGY, AND SUBUNIT. 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 [20] RP STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), FUNCTION, SUBCELLULAR RP LOCATION, TOPOLOGY, SUBUNIT, DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-45; RP ASN-55; ASN-187; ASN-264; ASN-387; ASN-435; ASN-464; ASN-506; ASN-530; RP ASN-562 AND ASN-573. 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 [21] RP STRUCTURE BY ELECTRON MICROSCOPY (4.40 ANGSTROMS) OF 42-665, DISULFIDE RP BONDS, SUBCELLULAR LOCATION, TOPOLOGY, AND SUBUNIT. 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 [22] RP STRUCTURE BY NMR OF 664-709, AND SUBCELLULAR LOCATION. RX PubMed=26776682; DOI=10.1038/srep19522; RA Li Y., Liew L.S., Li Q., Kang C.; RT "Structure of the transmembrane domain of human nicastrin-a component of RT gamma-secretase."; RL Sci. Rep. 6:19522-19522(2016). RN [23] {ECO:0007744|PDB:6IDF} RP STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS) IN COMPLEX WITH NOTCH1; RP PSENEN; APH1A AND PSEN1, FUNCTION, SUBUNIT, TOPOLOGY, GLYCOSYLATION AT RP ASN-45; ASN-55; ASN-187; ASN-264; ASN-387; ASN-435; ASN-464; ASN-506; RP ASN-530; ASN-562 AND ASN-573, DISULFIDE BOND, AND MUTAGENESIS OF TRP-653. 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 [24] {ECO:0007744|PDB:6IYC} RP STRUCTURE BY ELECTRON MICROSCOPY (2.60 ANGSTROMS) IN COMPLEX WITH APP CHAIN RP C83; PSENEN; APH1A AND PSEN1, FUNCTION, SUBUNIT, TOPOLOGY, GLYCOSYLATION AT RP ASN-45; ASN-55; ASN-187; ASN-264; ASN-387; ASN-435; ASN-464; ASN-506; RP ASN-530; ASN-562; ASN-573 AND ASN-580, AND DISULFIDE BOND. 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 [25] RP INVOLVEMENT IN ACNINV1. 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 [26] RP INVOLVEMENT IN ACNINV1. RX PubMed=21430701; DOI=10.1038/jid.2011.62; RA Liu Y., Gao M., Lv Y.M., Yang X., Ren Y.Q., Jiang T., Zhang X., Guo B.R., RA Li M., Zhang Q., Zhang P., Zhou F.S., Chen G., Yin X.Y., Zuo X.B., RA Sun L.D., Zheng X.D., Zhang S.M., Liu J.J., Zhou Y., Li Y.R., Wang J., RA Wang J., Yang H.M., Yang S., Li R.Q., Zhang X.J.; RT "Confirmation by exome sequencing of the pathogenic role of NCSTN mutations RT in acne inversa (hidradenitis suppurativa)."; RL J. Invest. Dermatol. 131:1570-1572(2011). RN [27] RP VARIANT ACNINV1 ARG-211. RX PubMed=21495993; DOI=10.1111/j.1365-2133.2011.10372.x; RA Li C.R., Jiang M.J., Shen D.B., Xu H.X., Wang H.S., Yao X., Zhang Y., RA Zhou W.Q., Wang B.; RT "Two novel mutations of the nicastrin gene in Chinese patients with acne RT inversa."; RL Br. J. Dermatol. 165:415-418(2011). CC -!- FUNCTION: Essential 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:10993067, PubMed:12679784, CC PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). CC The gamma-secretase complex plays a role in Notch and Wnt signaling CC cascades and regulation of downstream processes via its role in CC processing key regulatory proteins, and by regulating cytosolic CTNNB1 CC levels. {ECO:0000269|PubMed:10993067, ECO:0000269|PubMed:12679784, CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:26280335, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. CC -!- SUBUNIT: Component of the gamma-secretase complex (PubMed:10993067, CC PubMed:30598546, PubMed:30630874). The functional gamma-secretase CC complex is composed of at least four polypeptides: a presenilin CC homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) CC and PSENEN/PEN2 (PubMed:12740439, PubMed:25043039, PubMed:26623517, CC PubMed:26280335, PubMed:25918421, PubMed:30598546, PubMed:30630874). CC Binds to proteolytic processed C-terminal fragments C83 and C99 of the CC amyloid precursor protein (APP) (PubMed:10993067, PubMed:30630874). CC Interacts with PSEN1 and PSEN2 (PubMed:10993067). CC {ECO:0000269|PubMed:10993067, ECO:0000269|PubMed:12740439, 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}. CC -!- INTERACTION: CC Q92542; Q96BI3: APH1A; NbExp=4; IntAct=EBI-998440, EBI-2606935; CC Q92542; P35613: BSG; NbExp=6; IntAct=EBI-998440, EBI-750709; CC Q92542; P49768: PSEN1; NbExp=6; IntAct=EBI-998440, EBI-297277; CC Q92542; PRO_0000025592 [P49768]: PSEN1; NbExp=2; IntAct=EBI-998440, EBI-2606356; CC Q92542; Q9NZ42: PSENEN; NbExp=4; IntAct=EBI-998440, EBI-998468; CC Q92542; P49755: TMED10; NbExp=5; IntAct=EBI-998440, EBI-998422; CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000269|PubMed:10993067, CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25918421, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26623517, CC ECO:0000269|PubMed:26776682}; Single-pass type I 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 vesicle membrane {ECO:0000269|PubMed:10993067}; Single-pass type I CC membrane protein {ECO:0000269|PubMed:25043039, CC ECO:0000269|PubMed:25918421, ECO:0000269|PubMed:26280335, CC ECO:0000269|PubMed:26623517, ECO:0000269|PubMed:30598546, CC ECO:0000269|PubMed:30630874}. Melanosome {ECO:0000269|PubMed:12643545, CC ECO:0000269|PubMed:17081065}. Note=Identified by mass spectrometry in CC melanosome fractions from stage I to stage IV. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q92542-1; Sequence=Displayed; CC Name=2; CC IsoId=Q92542-2; Sequence=VSP_008385, VSP_008386; CC -!- TISSUE SPECIFICITY: Detected in brain (at protein level) CC (PubMed:10993067). Widely expressed (PubMed:11396676). CC {ECO:0000269|PubMed:10993067, ECO:0000269|PubMed:11396676}. CC -!- INDUCTION: Constitutively expressed in neural cells. CC {ECO:0000269|PubMed:11396676}. CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:10993067, CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:26280335, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. CC -!- DISEASE: Acne inversa, familial, 1 (ACNINV1) [MIM:142690]: 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, ECO:0000269|PubMed:21430701, CC ECO:0000269|PubMed:21495993}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the nicastrin family. {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; AF240468; AAG11412.1; -; mRNA. DR EMBL; AY359120; AAQ89478.1; -; mRNA. DR EMBL; AK314764; BAG37302.1; -; mRNA. DR EMBL; AL445230; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471121; EAW52720.1; -; Genomic_DNA. DR EMBL; CH471121; EAW52721.1; -; Genomic_DNA. DR EMBL; CH471121; EAW52722.1; -; Genomic_DNA. DR EMBL; BC047621; AAH47621.1; -; mRNA. DR EMBL; D87442; BAA13383.1; -; mRNA. DR CCDS; CCDS1203.1; -. [Q92542-1] DR RefSeq; NP_001277113.1; NM_001290184.1. [Q92542-2] DR RefSeq; NP_001277115.1; NM_001290186.1. DR RefSeq; NP_056146.1; NM_015331.2. [Q92542-1] DR PDB; 2N7Q; NMR; -; A=664-709. DR PDB; 2N7R; NMR; -; A=664-709. DR PDB; 4UIS; EM; 4.40 A; A=42-665. DR PDB; 5A63; EM; 3.40 A; A=1-709. DR PDB; 5FN2; EM; 4.20 A; A=1-709. DR PDB; 5FN3; EM; 4.10 A; A=1-709. DR PDB; 5FN4; EM; 4.00 A; A=1-709. DR PDB; 5FN5; EM; 4.30 A; A=1-709. DR PDB; 6IDF; EM; 2.70 A; A=1-709. DR PDB; 6IYC; EM; 2.60 A; A=1-709. DR PDB; 6LQG; EM; 3.10 A; A=1-709. DR PDB; 6LR4; EM; 3.00 A; A=1-709. DR PDB; 7C9I; EM; 3.10 A; A=1-709. DR PDB; 7D8X; EM; 2.60 A; A=1-709. DR PDB; 7Y5T; EM; 2.90 A; A=1-709. DR PDB; 7Y5X; EM; 3.00 A; A=1-709. DR PDB; 7Y5Z; EM; 3.40 A; A=1-709. DR PDBsum; 2N7Q; -. DR PDBsum; 2N7R; -. 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; 7Y5X; -. DR PDBsum; 7Y5Z; -. DR AlphaFoldDB; Q92542; -. DR EMDB; EMD-0944; -. DR EMDB; EMD-0957; -. DR EMDB; EMD-2477; -. DR EMDB; EMD-2478; -. DR EMDB; EMD-30312; -. DR EMDB; EMD-30614; -. DR EMDB; EMD-33624; -. DR EMDB; EMD-33628; -. DR EMDB; EMD-33629; -. DR EMDB; EMD-9648; -. DR EMDB; EMD-9751; -. DR SMR; Q92542; -. DR BioGRID; 116961; 185. DR ComplexPortal; CPX-2176; Gamma-secretase complex, APH1A-PSEN1 variant. DR ComplexPortal; CPX-4231; Gamma-secretase complex, APH1A-PSEN2 variant. DR ComplexPortal; CPX-4232; Gamma-secretase complex, APH1B-PSEN2 variant. DR ComplexPortal; CPX-4233; Gamma-secretase complex, APH1B-PSEN1 variant. DR CORUM; Q92542; -. DR DIP; DIP-36336N; -. DR IntAct; Q92542; 91. DR MINT; Q92542; -. DR STRING; 9606.ENSP00000294785; -. DR BindingDB; Q92542; -. DR ChEMBL; CHEMBL3418; -. DR GlyConnect; 1567; 6 N-Linked glycans (7 sites). DR GlyCosmos; Q92542; 17 sites, 6 glycans. DR GlyGen; Q92542; 24 sites, 7 N-linked glycans (8 sites), 1 O-linked glycan (5 sites). DR iPTMnet; Q92542; -. DR PhosphoSitePlus; Q92542; -. DR SwissPalm; Q92542; -. DR BioMuta; NCSTN; -. DR DMDM; 12231037; -. DR EPD; Q92542; -. DR jPOST; Q92542; -. DR MassIVE; Q92542; -. DR MaxQB; Q92542; -. DR PaxDb; 9606-ENSP00000294785; -. DR PeptideAtlas; Q92542; -. DR ProteomicsDB; 75302; -. [Q92542-1] DR ProteomicsDB; 75303; -. [Q92542-2] DR Pumba; Q92542; -. DR TopDownProteomics; Q92542-2; -. [Q92542-2] DR Antibodypedia; 20490; 596 antibodies from 44 providers. DR DNASU; 23385; -. DR Ensembl; ENST00000294785.10; ENSP00000294785.5; ENSG00000162736.18. [Q92542-1] DR GeneID; 23385; -. DR KEGG; hsa:23385; -. DR MANE-Select; ENST00000294785.10; ENSP00000294785.5; NM_015331.3; NP_056146.1. DR UCSC; uc001fvx.4; human. [Q92542-1] DR AGR; HGNC:17091; -. DR CTD; 23385; -. DR DisGeNET; 23385; -. DR GeneCards; NCSTN; -. DR HGNC; HGNC:17091; NCSTN. DR HPA; ENSG00000162736; Low tissue specificity. DR MalaCards; NCSTN; -. DR MIM; 142690; phenotype. DR MIM; 605254; gene. DR neXtProt; NX_Q92542; -. DR OpenTargets; ENSG00000162736; -. DR Orphanet; 387; NON RARE IN EUROPE: Hidradenitis suppurativa. DR PharmGKB; PA142671271; -. DR VEuPathDB; HostDB:ENSG00000162736; -. DR eggNOG; KOG2657; Eukaryota. DR GeneTree; ENSGT00390000014633; -. DR HOGENOM; CLU_024257_0_0_1; -. DR InParanoid; Q92542; -. DR OMA; ECVYPGV; -. DR OrthoDB; 1330770at2759; -. DR PhylomeDB; Q92542; -. DR TreeFam; TF317086; -. DR PathwayCommons; Q92542; -. 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-977225; Amyloid fiber formation. DR SignaLink; Q92542; -. DR SIGNOR; Q92542; -. DR BioGRID-ORCS; 23385; 43 hits in 1155 CRISPR screens. DR ChiTaRS; NCSTN; human. DR GeneWiki; Nicastrin; -. DR GenomeRNAi; 23385; -. DR Pharos; Q92542; Tbio. DR PRO; PR:Q92542; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q92542; Protein. DR Bgee; ENSG00000162736; Expressed in stromal cell of endometrium and 200 other cell types or tissues. DR ExpressionAtlas; Q92542; baseline and differential. DR GO; GO:0035577; C:azurophil granule membrane; TAS:Reactome. 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; NAS:ComplexPortal. DR GO; GO:0010008; C:endosome membrane; TAS:Reactome. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005925; C:focal adhesion; HDA: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; NAS:ComplexPortal. DR GO; GO:0005765; C:lysosomal membrane; HDA:UniProtKB. DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell. DR GO; GO:0016020; C: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:0042383; C:sarcolemma; IEA:Ensembl. DR GO; GO:0008021; C:synaptic vesicle; IEA:Ensembl. DR GO; GO:0042500; F:aspartic endopeptidase activity, intramembrane cleaving; IEA:Ensembl. DR GO; GO:0051117; F:ATPase binding; IPI:ARUK-UCL. DR GO; GO:0070851; F:growth factor receptor binding; IPI:ARUK-UCL. DR GO; GO:0030674; F:protein-macromolecule adaptor activity; IMP:ARUK-UCL. DR GO; GO:0030534; P:adult behavior; IEA:Ensembl. DR GO; GO:0042983; P:amyloid precursor protein biosynthetic process; IEA:Ensembl. 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:0071277; P:cellular response to calcium ion; IEA:Ensembl. DR GO; GO:0022010; P:central nervous system myelination; IEA:Ensembl. DR GO; GO:0021549; P:cerebellum development; IEA:Ensembl. DR GO; GO:0007212; P:dopamine receptor signaling pathway; IEA:Ensembl. DR GO; GO:0050673; P:epithelial cell proliferation; IEA:Ensembl. DR GO; GO:0007215; P:glutamate receptor signaling pathway; IEA:Ensembl. DR GO; GO:0007611; P:learning or memory; IEA:Ensembl. DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:HGNC-UCL. DR GO; GO:0031293; P:membrane protein intracellular domain proteolysis; IDA:ComplexPortal. DR GO; GO:0002262; P:myeloid cell homeostasis; IEA:Ensembl. DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl. DR GO; GO:0007220; P:Notch receptor processing; IDA:ARUK-UCL. DR GO; GO:0007219; P:Notch signaling pathway; IEA:UniProtKB-KW. DR GO; GO:0042986; P:positive regulation of amyloid precursor protein biosynthetic process; IEA:Ensembl. DR GO; GO:0043085; P:positive regulation of catalytic activity; IDA:HGNC-UCL. DR GO; GO:0010950; P:positive regulation of endopeptidase activity; IMP:ARUK-UCL. DR GO; GO:0016485; P:protein processing; IDA:HGNC-UCL. DR GO; GO:0006508; P:proteolysis; NAS:UniProtKB. DR GO; GO:1900271; P:regulation of long-term synaptic potentiation; IEA:Ensembl. DR GO; GO:1990926; P:short-term synaptic potentiation; IEA:Ensembl. DR GO; GO:0042098; P:T cell proliferation; IEA:Ensembl. DR CDD; cd03881; M28_Nicastrin; 1. DR Gene3D; 3.40.630.10; Zn peptidases; 1. DR InterPro; IPR041084; Ncstrn_small. DR InterPro; IPR008710; Nicastrin. DR PANTHER; PTHR21092; NICASTRIN; 1. DR PANTHER; PTHR21092:SF0; NICASTRIN; 1. DR Pfam; PF18266; Ncstrn_small; 1. DR Pfam; PF05450; Nicastrin; 1. DR SUPFAM; SSF53187; Zn-dependent exopeptidases; 1. DR Genevisible; Q92542; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasmic vesicle; Disease variant; KW Disulfide bond; Glycoprotein; Membrane; Notch signaling pathway; KW Reference proteome; Signal; Transmembrane; Transmembrane helix. FT SIGNAL 1..33 FT /evidence="ECO:0000255" FT CHAIN 34..709 FT /note="Nicastrin" FT /id="PRO_0000019681" FT TOPO_DOM 34..669 FT /note="Extracellular" FT /evidence="ECO:0000305|PubMed:26280335, FT ECO:0000305|PubMed:26776682" FT TRANSMEM 670..690 FT /note="Helical" FT /evidence="ECO:0000305|PubMed:26280335, FT ECO:0000305|PubMed:26776682" FT TOPO_DOM 691..709 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26280335, FT ECO:0000305|PubMed:26776682" FT CARBOHYD 45 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218, FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874, ECO:0007744|PDB:5A63, FT ECO:0007744|PDB:6IDF, ECO:0007744|PDB:6IYC" FT CARBOHYD 55 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255, ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, FT ECO:0007744|PDB:5A63, ECO:0007744|PDB:6IDF, FT ECO:0007744|PDB:6IYC" FT CARBOHYD 187 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218, FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874, ECO:0007744|PDB:5A63, FT ECO:0007744|PDB:6IDF, ECO:0007744|PDB:6IYC" FT CARBOHYD 200 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 204 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 264 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255, ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, FT ECO:0007744|PDB:5A63, ECO:0007744|PDB:6IDF, FT ECO:0007744|PDB:6IYC" FT CARBOHYD 387 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:12754519, FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, FT ECO:0007744|PDB:5A63, ECO:0007744|PDB:6IDF, FT ECO:0007744|PDB:6IYC" FT CARBOHYD 417 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 435 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255, ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, FT ECO:0007744|PDB:5A63, ECO:0007744|PDB:6IDF, FT ECO:0007744|PDB:6IYC" FT CARBOHYD 464 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255, ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, FT ECO:0007744|PDB:5A63, ECO:0007744|PDB:6IDF, FT ECO:0007744|PDB:6IYC" FT CARBOHYD 506 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255, ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, FT ECO:0007744|PDB:5A63, ECO:0007744|PDB:6IDF, FT ECO:0007744|PDB:6IYC" FT CARBOHYD 530 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255, ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, FT ECO:0007744|PDB:5A63, ECO:0007744|PDB:6IDF, FT ECO:0007744|PDB:6IYC" FT CARBOHYD 562 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255, ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, FT ECO:0007744|PDB:5A63, ECO:0007744|PDB:6IDF, FT ECO:0007744|PDB:6IYC" FT CARBOHYD 573 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255, ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, FT ECO:0007744|PDB:5A63, ECO:0007744|PDB:6IDF, FT ECO:0007744|PDB:6IYC" FT CARBOHYD 580 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:30630874, FT ECO:0007744|PDB:6IYC" FT CARBOHYD 612 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19349973" FT DISULFID 50..62 FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:26623517, ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874, ECO:0000305|PubMed:25043039, FT ECO:0000305|PubMed:25918421, ECO:0007744|PDB:4UIS, FT ECO:0007744|PDB:5A63, ECO:0007744|PDB:5FN2, FT ECO:0007744|PDB:5FN3, ECO:0007744|PDB:5FN4, FT ECO:0007744|PDB:5FN5, ECO:0007744|PDB:6IDF, FT ECO:0007744|PDB:6IYC" FT DISULFID 140..159 FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:26623517, ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874, ECO:0007744|PDB:5A63, FT ECO:0007744|PDB:5FN2, ECO:0007744|PDB:5FN3, FT ECO:0007744|PDB:5FN4, ECO:0007744|PDB:5FN5, FT ECO:0007744|PDB:6IDF, ECO:0007744|PDB:6IYC" FT DISULFID 195..213 FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:26623517, ECO:0000305|PubMed:25918421, FT ECO:0007744|PDB:4UIS, ECO:0007744|PDB:5A63, FT ECO:0007744|PDB:5FN2, ECO:0007744|PDB:5FN3, FT ECO:0007744|PDB:5FN4, ECO:0007744|PDB:5FN5" FT DISULFID 230..248 FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:26623517, ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874, ECO:0000305|PubMed:25918421, FT ECO:0007744|PDB:4UIS, ECO:0007744|PDB:5A63, FT ECO:0007744|PDB:5FN2, ECO:0007744|PDB:5FN3, FT ECO:0007744|PDB:5FN4, ECO:0007744|PDB:5FN5, FT ECO:0007744|PDB:6IDF, ECO:0007744|PDB:6IYC" FT DISULFID 586..620 FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000269|PubMed:26623517, ECO:0000269|PubMed:30598546, FT ECO:0000269|PubMed:30630874, ECO:0007744|PDB:5A63, FT ECO:0007744|PDB:5FN2, ECO:0007744|PDB:5FN3, FT ECO:0007744|PDB:5FN4, ECO:0007744|PDB:5FN5, FT ECO:0007744|PDB:6IDF, ECO:0007744|PDB:6IYC" FT VAR_SEQ 1..20 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_008385" FT VAR_SEQ 21..29 FT /note="LSFCVLLAG -> MDFNLILES (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_008386" FT VARIANT 75 FT /note="V -> I (in dbSNP:rs12045198)" FT /id="VAR_050274" FT VARIANT 77 FT /note="E -> D (in dbSNP:rs35603924)" FT /id="VAR_050275" FT VARIANT 211 FT /note="P -> R (in ACNINV1)" FT /evidence="ECO:0000269|PubMed:21495993" FT /id="VAR_067756" FT MUTAGEN 336..337 FT /note="DY->AA: Increases production of amyloid-beta FT (beta-APP40 and beta-APP42) in APP processing." FT /evidence="ECO:0000269|PubMed:10993067" FT MUTAGEN 653 FT /note="W->A,F: No effect on gamma-secretase activity." FT /evidence="ECO:0000269|PubMed:30598546" FT CONFLICT 657 FT /note="R -> H (in Ref. 6; AAH47621)" FT /evidence="ECO:0000305" FT HELIX 37..39 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 42..44 FT /evidence="ECO:0007829|PDB:6IDF" FT STRAND 46..49 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 59..61 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 69..76 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 78..80 FT /evidence="ECO:0007829|PDB:6IDF" FT HELIX 81..86 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 93..99 FT /evidence="ECO:0007829|PDB:6IYC" FT TURN 100..102 FT /evidence="ECO:0007829|PDB:5A63" FT HELIX 105..113 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 117..124 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 139..142 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 143..145 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 150..152 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 154..156 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 159..161 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 171..173 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 174..178 FT /evidence="ECO:0007829|PDB:5A63" FT STRAND 180..183 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 186..199 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 203..205 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 212..218 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 220..222 FT /evidence="ECO:0007829|PDB:5A63" FT HELIX 227..239 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 240..243 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 248..250 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 253..261 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 265..267 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 271..273 FT /evidence="ECO:0007829|PDB:5A63" FT STRAND 275..281 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 287..290 FT /evidence="ECO:0007829|PDB:6LR4" FT TURN 295..298 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 299..313 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 316..318 FT /evidence="ECO:0007829|PDB:6IDF" FT STRAND 322..331 FT /evidence="ECO:0007829|PDB:6IYC" FT TURN 334..336 FT /evidence="ECO:0007829|PDB:7D8X" FT HELIX 338..348 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 352..354 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 356..365 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 374..379 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 383..386 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 388..404 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 405..407 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 412..414 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 417..419 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 427..433 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 437..443 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 445..447 FT /evidence="ECO:0007829|PDB:6IYC" FT TURN 451..454 FT /evidence="ECO:0007829|PDB:6IYC" FT TURN 460..464 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 473..476 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 482..501 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 508..510 FT /evidence="ECO:0007829|PDB:7D8X" FT HELIX 515..526 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 529..532 FT /evidence="ECO:0007829|PDB:5A63" FT HELIX 534..536 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 540..545 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 557..560 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 562..575 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 577..579 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 583..587 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 589..591 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 592..594 FT /evidence="ECO:0007829|PDB:6IYC" FT TURN 597..599 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 600..605 FT /evidence="ECO:0007829|PDB:6IYC" FT TURN 611..614 FT /evidence="ECO:0007829|PDB:5A63" FT STRAND 619..623 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 626..630 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 633..635 FT /evidence="ECO:0007829|PDB:6IYC" FT TURN 636..638 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 643..645 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 649..651 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 652..654 FT /evidence="ECO:0007829|PDB:6IDF" FT STRAND 657..663 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 666..692 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 694..697 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 698..700 FT /evidence="ECO:0007829|PDB:2N7R" FT HELIX 704..706 FT /evidence="ECO:0007829|PDB:2N7Q" SQ SEQUENCE 709 AA; 78411 MW; C8C0EAEAD89E976A CRC64; MATAGGGSGA DPGSRGLLRL LSFCVLLAGL CRGNSVERKI YIPLNKTAPC VRLLNATHQI GCQSSISGDT GVIHVVEKEE DLQWVLTDGP NPPYMVLLES KHFTRDLMEK LKGRTSRIAG LAVSLTKPSP ASGFSPSVQC PNDGFGVYSN SYGPEFAHCR EIQWNSLGNG LAYEDFSFPI FLLEDENETK VIKQCYQDHN LSQNGSAPTF PLCAMQLFSH MHAVISTATC MRRSSIQSTF SINPEIVCDP LSDYNVWSML KPINTTGTLK PDDRVVVAAT RLDSRSFFWN VAPGAESAVA SFVTQLAAAE ALQKAPDVTT LPRNVMFVFF QGETFDYIGS SRMVYDMEKG KFPVQLENVD SFVELGQVAL RTSLELWMHT DPVSQKNESV RNQVEDLLAT LEKSGAGVPA VILRRPNQSQ PLPPSSLQRF LRARNISGVV LADHSGAFHN KYYQSIYDTA ENINVSYPEW LSPEEDLNFV TDTAKALADV ATVLGRALYE LAGGTNFSDT VQADPQTVTR LLYGFLIKAN NSWFQSILRQ DLRSYLGDGP LQHYIAVSSP TNTTYVVQYA LANLTGTVVN LTREQCQDPS KVPSENKDLY EYSWVQGPLH SNETDRLPRC VRSTARLARA LSPAFELSQW SSTEYSTWTE SRWKDIRARI FLIASKELEL ITLTVGFGIL IFSLIVTYCI NAKADVLFIA PREPGAVSY //