NICA_HUMAN
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 03-AUG-2022, entry version 200.
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}.
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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 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 AlphaFoldDB; Q92542; -.
DR SMR; Q92542; -.
DR BioGRID; 116961; 171.
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; 88.
DR MINT; Q92542; -.
DR STRING; 9606.ENSP00000294785; -.
DR BindingDB; Q92542; -.
DR ChEMBL; CHEMBL3418; -.
DR GlyConnect; 1567; 6 N-Linked glycans (7 sites).
DR GlyGen; Q92542; 20 sites, 7 N-linked glycans (8 sites), 1 O-linked glycan (1 site).
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; Q92542; -.
DR PeptideAtlas; Q92542; -.
DR PRIDE; Q92542; -.
DR ProteomicsDB; 75302; -. [Q92542-1]
DR ProteomicsDB; 75303; -. [Q92542-2]
DR TopDownProteomics; Q92542-2; -. [Q92542-2]
DR Antibodypedia; 20490; 543 antibodies from 44 providers.
DR DNASU; 23385; -.
DR Ensembl; ENST00000294785.10; ENSP00000294785.5; ENSG00000162736.17. [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 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; CMRRNSI; -.
DR OrthoDB; 777987at2759; -.
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; 32 hits in 1078 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 198 other tissues.
DR ExpressionAtlas; Q92542; baseline and differential.
DR Genevisible; Q92542; HS.
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; IC: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; IC:ComplexPortal.
DR GO; GO:0016021; C:integral component of membrane; IDA:UniProtKB.
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:0005765; C:lysosomal membrane; HDA:UniProtKB.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IDA:ComplexPortal.
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 InterPro; IPR041084; Ncstrn_small.
DR InterPro; IPR008710; Nicastrin.
DR PANTHER; PTHR21092; PTHR21092; 1.
DR Pfam; PF18266; Ncstrn_small; 1.
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 (beta-
FT 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
