ID APH1A_HUMAN Reviewed; 265 AA. AC Q96BI3; B4DQK0; Q5TB22; Q5TB23; Q969R6; Q9BVG0; Q9Y386; DT 26-SEP-2003, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 24-JAN-2024, entry version 186. DE RecName: Full=Gamma-secretase subunit APH-1A; DE Short=APH-1a; DE AltName: Full=Aph-1alpha; DE AltName: Full=Presenilin-stabilization factor; GN Name=APH1A; Synonyms=PSF; ORFNames=CGI-78, UNQ579/PRO1141; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND INTERACTION WITH RP PSEN1; PSEN2 AND NCSTN. RC TISSUE=Glioblastoma; RX PubMed=12297508; DOI=10.1074/jbc.m208164200; RA Lee S.-F., Shah S., Li H., Yu C., Han W., Yu G.; RT "Mammalian APH-1 interacts with presenilin and nicastrin and is required RT for intramembrane proteolysis of amyloid-beta precursor protein and RT Notch."; RL J. Biol. Chem. 277:45013-45019(2002). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2). RA Lee H.-J., Kim T.-W.; RT "PSF is essential for gamma-secretase activity and stabilization of RT presenilin and nicastrin."; RL Submitted (MAY-2002) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RX PubMed=10810093; DOI=10.1101/gr.10.5.703; RA Lai C.-H., Chou C.-Y., Ch'ang L.-Y., Liu C.-S., Lin W.-C.; RT "Identification of novel human genes evolutionarily conserved in RT Caenorhabditis elegans by comparative proteomics."; RL Genome Res. 10:703-713(2000). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3). RC TISSUE=Retinoblastoma, and Thyroid; 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 (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Adrenal gland, Brain, Cervix, Eye, Glial tumor, and Lung; 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 TISSUE SPECIFICITY. RX PubMed=12110170; DOI=10.1016/s1534-5807(02)00189-2; RA Francis R., McGrath G., Zhang J., Ruddy D.A., Sym M., Apfeld J., Nicoll M., RA Maxwell M., Hai B., Ellis M.C., Parks A.L., Xu W., Li J., Gurney M., RA Myers R.L., Himes C.S., Hiebsch R., Ruble C., Nye J.S., Curtis D.; RT "aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase RT cleavage of betaAPP, and presenilin protein accumulation."; RL Dev. Cell 3:85-97(2002). RN [10] RP SUBCELLULAR LOCATION, AND FUNCTION. RX PubMed=12522139; DOI=10.1074/jbc.c200648200; RA Luo W.-J., Wang H., Li H., Kim B.S., Shah S., Lee H.-J., Thinakaran G., RA Kim T.-W., Yu G., Xu H.; RT "PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin RT 1."; RL J. Biol. Chem. 278:7850-7854(2003). RN [11] RP SUBCELLULAR LOCATION, AND INTERACTION WITH PSEN1. RX PubMed=12471034; DOI=10.1074/jbc.m209499200; RA Gu Y., Chen F., Sanjo N., Kawarai T., Hasegawa H., Duthie M., Li W., RA Ruan X., Luthra A., Mount H.T.J., Tandon A., Fraser P.E., RA St George-Hyslop P.H.; RT "APH-1 interacts with mature and immature forms of presenilins and RT nicastrin and may play a role in maturation of presenilin.nicastrin RT complexes."; RL J. Biol. Chem. 278:7374-7380(2003). RN [12] RP FUNCTION IN THE GAMMA-SECRETASE COMPLEX. RX PubMed=12763021; DOI=10.1016/s0006-291x(03)00797-6; RA Marlow L., Canet R.M., Haugabook S.J., Hardy J.A., Lahiri D.K., RA Sambamurti K.; RT "APH1, PEN2, and nicastrin increase Abeta levels and gamma-secretase RT activity."; RL Biochem. Biophys. Res. Commun. 305:502-509(2003). RN [13] RP COMPONENT OF A GAMMA-SECRETASE COMPLEX WITH PEN2; PSEN1/PSEN2 AND NCSTN, RP AND SUBUNIT. 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 [14] RP ENZYME ACTIVITY OF A GAMMA-SECRETASE COMPLEX, AND FUNCTION. 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 [15] RP SUBCELLULAR LOCATION, AND MEMBRANE TOPOLOGY. RX PubMed=14593096; DOI=10.1074/jbc.m310505200; RA Fortna R.R., Crystal A.S., Morais V.A., Pijak D.S., Lee V.M., Doms R.W.; RT "Membrane topology and nicastrin-enhanced endoproteolysis of APH-1, a RT component of the gamma-secretase complex."; RL J. Biol. Chem. 279:3685-3693(2004). RN [16] RP FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, AND MUTAGENESIS OF HIS-171 AND RP HIS-197. RX PubMed=19369254; DOI=10.1074/jbc.m109.000067; RA Pardossi-Piquard R., Yang S.P., Kanemoto S., Gu Y., Chen F., Boehm C., RA Sevalle J., Li T., Wong P.C., Checler F., Schmitt-Ulms G., RA St George-Hyslop P., Fraser P.E.; RT "APH1 polar transmembrane residues regulate the assembly and activity of RT presenilin complexes."; RL J. Biol. Chem. 284:16298-16307(2009). RN [17] RP STRUCTURE BY ELECTRON MICROSCOPY (4.5 ANGSTROMS), FUNCTION, SUBCELLULAR RP LOCATION, TOPOLOGY, AND SUBUNIT. 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 [18] RP STRUCTURE BY ELECTRON MICROSCOPY (4.00 ANGSTROMS), SUBCELLULAR LOCATION, RP TISSUE SPECIFICITY, 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 [19] RP STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), FUNCTION, SUBCELLULAR RP LOCATION, TOPOLOGY, AND SUBUNIT. 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 [20] RP STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS) IN COMPLEX WITH NOTCH1; RP PSENEN; PSEN1 AND NCSTN, FUNCTION, SUBUNIT, AND TOPOLOGY. 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 [21] RP STRUCTURE BY ELECTRON MICROSCOPY (2.60 ANGSTROMS) IN COMPLEX WITH APP CHAIN RP C83; PSENEN; PSEN1 AND NCSTN, FUNCTION, SUBUNIT, AND TOPOLOGY. 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). CC -!- FUNCTION: Non-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:12297508, PubMed:12522139, CC PubMed:12763021, PubMed:12679784, PubMed:25043039, PubMed:26280335, CC PubMed:30598546, PubMed:30630874). Required for normal gamma-secretase CC assembly (PubMed:12522139, PubMed:12471034, PubMed:12763021, CC PubMed:19369254). The gamma-secretase complex plays a role in Notch and CC Wnt signaling cascades and regulation of downstream processes via its CC role in processing key regulatory proteins, and by regulating cytosolic CC CTNNB1 levels (Probable). {ECO:0000269|PubMed:12297508, CC ECO:0000269|PubMed:12471034, ECO:0000269|PubMed:12522139, CC ECO:0000269|PubMed:12679784, ECO:0000269|PubMed:12763021, CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:26280335, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874, ECO:0000305}. CC -!- SUBUNIT: The functional gamma-secretase complex is composed of at least CC four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin CC (NCSTN), APH1 (APH1A or APH1B) and PSENEN/PEN2 (PubMed:12297508, CC PubMed:12740439, PubMed:19369254, PubMed:25043039, PubMed:26623517, CC PubMed:26280335, PubMed:30598546, PubMed:30630874). CC {ECO:0000269|PubMed:12297508, ECO:0000269|PubMed:12740439, CC ECO:0000269|PubMed:19369254, ECO:0000269|PubMed:25043039, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26623517, CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. CC -!- INTERACTION: CC Q96BI3; Q86W74-2: ANKRD46; NbExp=3; IntAct=EBI-2606935, EBI-12109402; CC Q96BI3; P05090: APOD; NbExp=3; IntAct=EBI-2606935, EBI-715495; CC Q96BI3; P05067: APP; NbExp=3; IntAct=EBI-2606935, EBI-77613; CC Q96BI3; P07306: ASGR1; NbExp=3; IntAct=EBI-2606935, EBI-1172335; CC Q96BI3; Q15438: CYTH1; NbExp=3; IntAct=EBI-2606935, EBI-997830; CC Q96BI3; Q9Y3D6: FIS1; NbExp=3; IntAct=EBI-2606935, EBI-3385283; CC Q96BI3; Q9H0Q3: FXYD6; NbExp=3; IntAct=EBI-2606935, EBI-713304; CC Q96BI3; P06241: FYN; NbExp=3; IntAct=EBI-2606935, EBI-515315; CC Q96BI3; P24593: IGFBP5; NbExp=3; IntAct=EBI-2606935, EBI-720480; CC Q96BI3; O43561-2: LAT; NbExp=3; IntAct=EBI-2606935, EBI-8070286; CC Q96BI3; Q6ZSS7: MFSD6; NbExp=3; IntAct=EBI-2606935, EBI-2858252; CC Q96BI3; Q00013: MPP1; NbExp=3; IntAct=EBI-2606935, EBI-711788; CC Q96BI3; Q96G30: MRAP2; NbExp=3; IntAct=EBI-2606935, EBI-9537218; CC Q96BI3; Q92542: NCSTN; NbExp=4; IntAct=EBI-2606935, EBI-998440; CC Q96BI3; P49768: PSEN1; NbExp=3; IntAct=EBI-2606935, EBI-297277; CC Q96BI3; P57086: SCAND1; NbExp=3; IntAct=EBI-2606935, EBI-745846; CC Q96BI3; Q9Y6X1: SERP1; NbExp=3; IntAct=EBI-2606935, EBI-10329948; CC Q96BI3; Q9NVC3: SLC38A7; NbExp=3; IntAct=EBI-2606935, EBI-10314552; CC Q96BI3; Q9NUM3: SLC39A9; NbExp=3; IntAct=EBI-2606935, EBI-2823239; CC Q96BI3; Q0VAQ4: SMAGP; NbExp=3; IntAct=EBI-2606935, EBI-10226799; CC Q96BI3; Q9NV12: TMEM140; NbExp=3; IntAct=EBI-2606935, EBI-2844246; CC Q96BI3; A2RU14: TMEM218; NbExp=3; IntAct=EBI-2606935, EBI-10173151; CC Q96BI3; A5PKU2: TUSC5; NbExp=3; IntAct=EBI-2606935, EBI-11988865; CC Q96BI3-2; P61158: ACTR3; NbExp=3; IntAct=EBI-25922794, EBI-351428; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:12522139}; Multi-pass membrane protein CC {ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:26280335, CC ECO:0000269|PubMed:26623517, ECO:0000269|PubMed:30598546, CC ECO:0000269|PubMed:30630874}. Golgi apparatus, Golgi stack membrane CC {ECO:0000269|PubMed:12522139}; Multi-pass membrane protein CC {ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:26280335, CC ECO:0000269|PubMed:26623517, ECO:0000269|PubMed:30598546, CC ECO:0000269|PubMed:30630874}. Note=Predominantly located in the CC endoplasmic reticulum and in the cis-Golgi. CC {ECO:0000269|PubMed:12522139}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; Synonyms=L, Aph-alpha1; CC IsoId=Q96BI3-1; Sequence=Displayed; CC Name=2; Synonyms=S, Aph-alpha2; CC IsoId=Q96BI3-2; Sequence=VSP_008355, VSP_008356; CC Name=3; CC IsoId=Q96BI3-3; Sequence=VSP_045424; CC -!- TISSUE SPECIFICITY: Widely expressed. Expressed in leukocytes, lung, CC placenta, small intestine, liver, kidney, spleen thymus, skeletal CC muscle, heart and brain. Isoform 1 and isoform 2 are nearly expressed CC at the same level. {ECO:0000269|PubMed:12110170}. CC -!- SIMILARITY: Belongs to the APH-1 family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAD34072.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=AAN63816.1; Type=Frameshift; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF508787; AAN63816.1; ALT_FRAME; mRNA. DR EMBL; AY113698; AAM61955.1; -; mRNA. DR EMBL; AY113699; AAM61956.1; -; mRNA. DR EMBL; AF151835; AAD34072.1; ALT_FRAME; mRNA. DR EMBL; AY358951; AAQ89310.1; -; mRNA. DR EMBL; AK027879; BAG51389.1; -; mRNA. DR EMBL; AK075295; BAC11529.1; -; mRNA. DR EMBL; AK298832; BAG60962.1; -; mRNA. DR EMBL; AL138795; CAI22811.1; -; Genomic_DNA. DR EMBL; AL138795; CAI22812.1; -; Genomic_DNA. DR EMBL; CH471121; EAW53565.1; -; Genomic_DNA. DR EMBL; CH471121; EAW53566.1; -; Genomic_DNA. DR EMBL; CH471121; EAW53567.1; -; Genomic_DNA. DR EMBL; BC001230; AAH01230.1; -; mRNA. DR EMBL; BC008732; AAH08732.1; -; mRNA. DR EMBL; BC009501; AAH09501.1; -; mRNA. DR EMBL; BC015568; AAH15568.1; -; mRNA. DR EMBL; BC017699; AAH17699.1; -; mRNA. DR EMBL; BC020590; AAH20590.1; -; mRNA. DR CCDS; CCDS41390.1; -. [Q96BI3-1] DR CCDS; CCDS41391.1; -. [Q96BI3-2] DR CCDS; CCDS58025.1; -. [Q96BI3-3] DR RefSeq; NP_001071096.1; NM_001077628.2. [Q96BI3-1] DR RefSeq; NP_001230700.1; NM_001243771.1. DR RefSeq; NP_001230701.1; NM_001243772.1. [Q96BI3-3] DR RefSeq; NP_057106.2; NM_016022.3. [Q96BI3-2] DR PDB; 5A63; EM; 3.40 A; C=1-265. DR PDB; 5FN2; EM; 4.20 A; C=1-265. DR PDB; 5FN3; EM; 4.10 A; C=1-265. DR PDB; 5FN4; EM; 4.00 A; C=1-265. DR PDB; 5FN5; EM; 4.30 A; C=1-265. DR PDB; 6IDF; EM; 2.70 A; C=1-265. DR PDB; 6IYC; EM; 2.60 A; C=1-265. DR PDB; 6LQG; EM; 3.10 A; C=1-265. DR PDB; 6LR4; EM; 3.00 A; C=1-265. DR PDB; 7C9I; EM; 3.10 A; C=1-265. DR PDB; 7D8X; EM; 2.60 A; C=1-265. DR PDB; 7Y5T; EM; 2.90 A; C=1-265. DR PDB; 7Y5X; EM; 3.00 A; C=1-265. DR PDB; 7Y5Z; EM; 3.40 A; C=1-265. 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; Q96BI3; -. DR EMDB; EMD-0944; -. DR EMDB; EMD-0957; -. DR EMDB; EMD-2477; -. DR EMDB; EMD-2478; -. DR EMDB; EMD-30312; -. DR EMDB; EMD-3061; -. DR EMDB; EMD-30614; -. DR EMDB; EMD-3237; -. DR EMDB; EMD-3238; -. DR EMDB; EMD-3239; -. DR EMDB; EMD-3240; -. DR EMDB; EMD-33624; -. DR EMDB; EMD-33628; -. DR EMDB; EMD-33629; -. DR EMDB; EMD-9648; -. DR EMDB; EMD-9751; -. DR SMR; Q96BI3; -. DR BioGRID; 119296; 63. DR ComplexPortal; CPX-2176; Gamma-secretase complex, APH1A-PSEN1 variant. DR ComplexPortal; CPX-4231; Gamma-secretase complex, APH1A-PSEN2 variant. DR CORUM; Q96BI3; -. DR DIP; DIP-44671N; -. DR IntAct; Q96BI3; 42. DR MINT; Q96BI3; -. DR STRING; 9606.ENSP00000358105; -. DR BindingDB; Q96BI3; -. DR ChEMBL; CHEMBL2094135; -. DR DrugBank; DB05171; E-2012. DR DrugBank; DB12852; MK-0752. DR TCDB; 1.A.121.1.2; the anterior pharynx-defective water channel (aph-wc) family. DR GlyGen; Q96BI3; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q96BI3; -. DR PhosphoSitePlus; Q96BI3; -. DR SwissPalm; Q96BI3; -. DR BioMuta; APH1A; -. DR DMDM; 37077707; -. DR EPD; Q96BI3; -. DR jPOST; Q96BI3; -. DR MassIVE; Q96BI3; -. DR MaxQB; Q96BI3; -. DR PaxDb; 9606-ENSP00000358105; -. DR PeptideAtlas; Q96BI3; -. DR ProteomicsDB; 4885; -. DR ProteomicsDB; 76078; -. [Q96BI3-1] DR ProteomicsDB; 76079; -. [Q96BI3-2] DR Pumba; Q96BI3; -. DR TopDownProteomics; Q96BI3-2; -. [Q96BI3-2] DR Antibodypedia; 34020; 408 antibodies from 37 providers. DR DNASU; 51107; -. DR Ensembl; ENST00000360244.8; ENSP00000353380.4; ENSG00000117362.13. [Q96BI3-2] DR Ensembl; ENST00000369109.8; ENSP00000358105.3; ENSG00000117362.13. [Q96BI3-1] DR Ensembl; ENST00000414276.6; ENSP00000397473.2; ENSG00000117362.13. [Q96BI3-3] DR GeneID; 51107; -. DR KEGG; hsa:51107; -. DR MANE-Select; ENST00000369109.8; ENSP00000358105.3; NM_001077628.3; NP_001071096.1. DR UCSC; uc001ety.3; human. [Q96BI3-1] DR AGR; HGNC:29509; -. DR CTD; 51107; -. DR DisGeNET; 51107; -. DR GeneCards; APH1A; -. DR HGNC; HGNC:29509; APH1A. DR HPA; ENSG00000117362; Low tissue specificity. DR MIM; 607629; gene. DR neXtProt; NX_Q96BI3; -. DR OpenTargets; ENSG00000117362; -. DR PharmGKB; PA142672599; -. DR VEuPathDB; HostDB:ENSG00000117362; -. DR eggNOG; KOG3972; Eukaryota. DR GeneTree; ENSGT00390000002049; -. DR HOGENOM; CLU_086389_0_0_1; -. DR InParanoid; Q96BI3; -. DR OMA; DTNNYLH; -. DR OrthoDB; 5693at2759; -. DR PhylomeDB; Q96BI3; -. DR TreeFam; TF314362; -. DR PathwayCommons; Q96BI3; -. 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-977225; Amyloid fiber formation. DR SignaLink; Q96BI3; -. DR SIGNOR; Q96BI3; -. DR BioGRID-ORCS; 51107; 14 hits in 1154 CRISPR screens. DR ChiTaRS; APH1A; human. DR GenomeRNAi; 51107; -. DR Pharos; Q96BI3; Tbio. DR PRO; PR:Q96BI3; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q96BI3; Protein. DR Bgee; ENSG00000117362; Expressed in skin of leg and 197 other cell types or tissues. DR ExpressionAtlas; Q96BI3; baseline and differential. 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:0070765; C:gamma-secretase complex; IDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; IDA:HGNC-UCL. DR GO; GO:0032580; C:Golgi cisterna membrane; IEA:UniProtKB-SubCell. DR GO; GO:0000139; C:Golgi membrane; NAS:ComplexPortal. 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:0008021; C:synaptic vesicle; IEA:Ensembl. DR GO; GO:0061133; F:endopeptidase activator activity; IMP:ARUK-UCL. DR GO; GO:0019899; F:enzyme binding; IEA:Ensembl. DR GO; GO:0030674; F:protein-macromolecule adaptor activity; IMP:ARUK-UCL. 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:0006509; P:membrane protein ectodomain proteolysis; IDA:HGNC-UCL. DR GO; GO:0031293; P:membrane protein intracellular domain proteolysis; IDA:ComplexPortal. DR GO; GO:0001656; P:metanephros development; IEA:Ensembl. DR GO; GO:0007220; P:Notch receptor processing; IDA:ARUK-UCL. DR GO; GO:0007219; P:Notch signaling pathway; IBA:GO_Central. DR GO; GO: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 InterPro; IPR009294; Aph-1. DR PANTHER; PTHR12889; GAMMA-SECRETASE SUBUNIT APH-1; 1. DR PANTHER; PTHR12889:SF3; GAMMA-SECRETASE SUBUNIT APH-1A; 1. DR Pfam; PF06105; Aph-1; 1. DR Genevisible; Q96BI3; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Endoplasmic reticulum; Golgi apparatus; KW Membrane; Notch signaling pathway; Reference proteome; Transmembrane; KW Transmembrane helix. FT CHAIN 1..265 FT /note="Gamma-secretase subunit APH-1A" FT /id="PRO_0000221050" FT TOPO_DOM 1..2 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000305|PubMed:14593096" FT TRANSMEM 3..23 FT /note="Helical; Name=1" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 24..31 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000305|PubMed:14593096" FT TRANSMEM 32..52 FT /note="Helical; Name=2" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 53..68 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000305|PubMed:14593096" FT TRANSMEM 69..89 FT /note="Helical; Name=3" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 90..118 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000305|PubMed:14593096" FT TRANSMEM 119..139 FT /note="Helical; Name=4" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 140..158 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000305|PubMed:14593096" FT TRANSMEM 159..179 FT /note="Helical; Name=5" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 180..186 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000305|PubMed:14593096" FT TRANSMEM 187..207 FT /note="Helical; Name=6" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 208..213 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000305|PubMed:14593096" FT TRANSMEM 214..234 FT /note="Helical; Name=7" FT /evidence="ECO:0000269|PubMed:26280335" FT TOPO_DOM 235..265 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:26280335, FT ECO:0000305|PubMed:14593096" FT VAR_SEQ 39..120 FT /note="AFFWLVSLLLASVVWFILVHVTDRSDARLQYGLLIFGAAVSVLLQEVFRFAY FT YKLLKKADEGLASLSEDGRSPISIRQMAYV -> RCSALPTTSCLI (in isoform FT 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_045424" FT VAR_SEQ 246..247 FT /note="RR -> KD (in isoform 2)" FT /evidence="ECO:0000303|PubMed:10810093, FT ECO:0000303|PubMed:12975309, ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334, ECO:0000303|Ref.2" FT /id="VSP_008355" FT VAR_SEQ 248..265 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:10810093, FT ECO:0000303|PubMed:12975309, ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334, ECO:0000303|Ref.2" FT /id="VSP_008356" FT MUTAGEN 171 FT /note="H->A: Impaired gamma-secretease assembly and reduced FT proteolytic activity of the gamma-secretase complex." FT /evidence="ECO:0000269|PubMed:19369254" FT MUTAGEN 197 FT /note="H->A: Impaired gamma-secretease assembly and reduced FT proteolytic activity of the gamma-secretase complex." FT /evidence="ECO:0000269|PubMed:19369254" FT CONFLICT 236 FT /note="L -> I (in Ref. 8; AAH01230)" FT /evidence="ECO:0000305" FT HELIX 3..13 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 15..23 FT /evidence="ECO:0007829|PDB:6IYC" FT TURN 24..27 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 31..60 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 66..102 FT /evidence="ECO:0007829|PDB:6IYC" FT STRAND 104..108 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 114..134 FT /evidence="ECO:0007829|PDB:6IYC" FT TURN 135..139 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 140..142 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 156..184 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 189..202 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 203..206 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 210..212 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 215..231 FT /evidence="ECO:0007829|PDB:6IYC" FT HELIX 236..240 FT /evidence="ECO:0007829|PDB:6IYC" SQ SEQUENCE 265 AA; 28996 MW; 8E37984A1DECC263 CRC64; MGAAVFFGCT FVAFGPAFAL FLITVAGDPL RVIILVAGAF FWLVSLLLAS VVWFILVHVT DRSDARLQYG LLIFGAAVSV LLQEVFRFAY YKLLKKADEG LASLSEDGRS PISIRQMAYV SGLSFGIISG VFSVINILAD ALGPGVVGIH GDSPYYFLTS AFLTAAIILL HTFWGVVFFD ACERRRYWAL GLVVGSHLLT SGLTFLNPWY EASLLPIYAV TVSMGLWAFI TAGGSLRSIQ RSLLCRRQED SRVMVYSALR IPPED //