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 16-OCT-2019, entry version 163. 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; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; 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 RT required for intramembrane proteolysis of amyloid-beta precursor RT protein and 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., RA Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., RA Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J., RA Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A., RA Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H., RA Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D., RA Wood W.I., Godowski P.J., Gray A.M.; RT "The secreted protein discovery initiative (SPDI), a large-scale RT effort to identify novel human secreted and transmembrane proteins: a RT bioinformatics 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., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA 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., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., 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., RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C., RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., RA 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., RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., RA 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., RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., RA 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., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA 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 RT project: 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., RA Nicoll M., Maxwell M., Hai B., Ellis M.C., Parks A.L., Xu W., Li J., RA Gurney M., Myers R.L., Himes C.S., Hiebsch R., Ruble C., Nye J.S., RA Curtis D.; RT "aph-1 and pen-2 are required for Notch pathway signaling, gamma- RT secretase 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., RA Thinakaran G., Kim T.-W., Yu G., Xu H.; RT "PEN-2 and APH-1 coordinately regulate proteolytic processing of RT presenilin 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 RP NCSTN, 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 RT presenilin, 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., RA 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 RP AND 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 RT of presenilin complexes."; RL J. Biol. Chem. 284:16298-16307(2009). RN [17] RP STRUCTURE BY ELECTRON MICROSCOPY (4.5 ANGSTROMS), FUNCTION, RP SUBCELLULAR 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., RA Zhou R., 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 RP LOCATION, 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 RT gamma-secretase."; RL Elife 4:0-0(2015). RN [19] RP STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), FUNCTION, RP SUBCELLULAR 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., RA Scheres S.H., 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 RP NOTCH1; 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 RP CHAIN 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- RT 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 CC (amyloid-beta precursor protein) (PubMed:12297508, CC PubMed:12522139, PubMed:12763021, PubMed:12679784, CC PubMed:25043039, PubMed:26280335, PubMed:30598546, CC PubMed:30630874). Required for normal gamma-secretase assembly CC (PubMed:12522139, PubMed:12471034, PubMed:12763021, CC PubMed:19369254). The gamma-secretase complex plays a role in CC Notch and Wnt signaling cascades and regulation of downstream CC processes via its role in processing key regulatory proteins, and CC by regulating cytosolic CTNNB1 levels (Probable). CC {ECO:0000269|PubMed:12297508, ECO:0000269|PubMed:12471034, CC ECO:0000269|PubMed:12522139, ECO:0000269|PubMed:12679784, CC ECO:0000269|PubMed:12763021, ECO:0000269|PubMed:25043039, CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:30598546, CC ECO:0000269|PubMed:30630874, ECO:0000305}. CC -!- SUBUNIT: The functional gamma-secretase complex is composed of at CC least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), CC nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN/PEN2 CC (PubMed:12297508, PubMed:12740439, PubMed:19369254, CC PubMed:25043039, PubMed:26623517, PubMed:26280335, CC PubMed:30598546, PubMed:30630874). {ECO:0000269|PubMed:12297508, CC ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:19369254, CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:26280335, CC ECO:0000269|PubMed:26623517, ECO:0000269|PubMed:30598546, CC ECO:0000269|PubMed:30630874}. CC -!- INTERACTION: CC Q92542:NCSTN; NbExp=4; IntAct=EBI-2606935, EBI-998440; 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 CC membrane {ECO:0000269|PubMed:12522139}; Multi-pass membrane CC protein {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, CC lung, placenta, small intestine, liver, kidney, spleen thymus, CC skeletal muscle, heart and brain. Isoform 1 and isoform 2 are CC nearly expressed 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 PDBsum; 5A63; -. DR PDBsum; 5FN2; -. DR PDBsum; 5FN3; -. DR PDBsum; 5FN4; -. DR PDBsum; 5FN5; -. DR PDBsum; 6IDF; -. DR PDBsum; 6IYC; -. DR SMR; Q96BI3; -. DR BioGrid; 119296; 23. 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; 35. DR MINT; Q96BI3; -. DR STRING; 9606.ENSP00000358105; -. DR BindingDB; Q96BI3; -. DR ChEMBL; CHEMBL2094135; -. DR DrugBank; DB05171; E-2012. 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; Q96BI3; -. DR PeptideAtlas; Q96BI3; -. DR PRIDE; Q96BI3; -. DR ProteomicsDB; 4885; -. DR ProteomicsDB; 76078; -. [Q96BI3-1] DR ProteomicsDB; 76079; -. [Q96BI3-2] DR TopDownProteomics; Q96BI3-2; -. [Q96BI3-2] DR DNASU; 51107; -. DR Ensembl; ENST00000360244; ENSP00000353380; ENSG00000117362. [Q96BI3-2] DR Ensembl; ENST00000369109; ENSP00000358105; ENSG00000117362. [Q96BI3-1] DR Ensembl; ENST00000414276; ENSP00000397473; ENSG00000117362. [Q96BI3-3] DR GeneID; 51107; -. DR KEGG; hsa:51107; -. DR UCSC; uc001ety.3; human. [Q96BI3-1] DR CTD; 51107; -. DR DisGeNET; 51107; -. DR GeneCards; APH1A; -. DR HGNC; HGNC:29509; APH1A. DR HPA; CAB037272; -. DR MIM; 607629; gene. DR neXtProt; NX_Q96BI3; -. DR OpenTargets; ENSG00000117362; -. DR PharmGKB; PA142672599; -. DR eggNOG; KOG3972; Eukaryota. DR eggNOG; ENOG4111FIJ; LUCA. DR GeneTree; ENSGT00390000002049; -. DR HOGENOM; HOG000007541; -. DR InParanoid; Q96BI3; -. DR KO; K06172; -. DR OMA; FFNAFDT; -. DR OrthoDB; 1085102at2759; -. DR PhylomeDB; Q96BI3; -. DR TreeFam; TF314362; -. 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 ChiTaRS; APH1A; human. DR GenomeRNAi; 51107; -. DR Pharos; Q96BI3; -. DR PRO; PR:Q96BI3; -. DR Proteomes; UP000005640; Chromosome 1. DR Bgee; ENSG00000117362; Expressed in 225 organ(s), highest expression level in skin of abdomen. DR ExpressionAtlas; Q96BI3; baseline and differential. DR Genevisible; Q96BI3; HS. DR GO; GO:0005769; C:early endosome; IEA:Ensembl. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HGNC. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. 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. DR GO; GO:0032580; C:Golgi cisterna membrane; IEA:UniProtKB-SubCell. DR GO; GO:0016021; C:integral component of membrane; IDA:UniProtKB. DR GO; GO:0005887; C:integral component of plasma membrane; IDA:HGNC. DR GO; GO:0099056; C:integral component of presynaptic membrane; IEA:Ensembl. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0008021; C:synaptic vesicle; IEA:Ensembl. DR GO; GO:0004175; F:endopeptidase activity; IBA:GO_Central. DR GO; GO:0042987; P:amyloid precursor protein catabolic process; IMP:UniProtKB. DR GO; GO:0042982; P:amyloid precursor protein metabolic process; IDA:UniProtKB. DR GO; GO:0034205; P:amyloid-beta formation; IMP:UniProtKB. DR GO; GO:0044267; P:cellular protein metabolic process; TAS:Reactome. DR GO; GO:0048013; P:ephrin receptor signaling pathway; TAS:Reactome. DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:HGNC. DR GO; GO:0031293; P:membrane protein intracellular domain proteolysis; IMP:UniProtKB. DR GO; GO:0001656; P:metanephros development; IEA:Ensembl. DR GO; GO:0007220; P:Notch receptor processing; IMP:UniProtKB. DR GO; GO:0035333; P:Notch receptor processing, ligand-dependent; TAS:Reactome. DR GO; GO:0007219; P:Notch signaling pathway; IBA:GO_Central. DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:Reactome. DR GO; GO:0043085; P:positive regulation of catalytic activity; IDA:HGNC. DR GO; GO:0016485; P:protein processing; IDA:HGNC. DR InterPro; IPR009294; Aph-1. DR PANTHER; PTHR12889; PTHR12889; 1. DR Pfam; PF06105; Aph-1; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Complete proteome; KW Endoplasmic reticulum; Golgi apparatus; Membrane; KW Notch signaling pathway; Reference proteome; Transmembrane; KW Transmembrane helix. FT CHAIN 1 265 Gamma-secretase subunit APH-1A. FT /FTId=PRO_0000221050. FT TOPO_DOM 1 2 Lumenal. {ECO:0000269|PubMed:26280335, FT ECO:0000305|PubMed:14593096}. FT TRANSMEM 3 23 Helical; Name=1. FT {ECO:0000269|PubMed:26280335}. FT TOPO_DOM 24 31 Cytoplasmic. FT {ECO:0000269|PubMed:26280335, FT ECO:0000305|PubMed:14593096}. FT TRANSMEM 32 52 Helical; Name=2. FT {ECO:0000269|PubMed:26280335}. FT TOPO_DOM 53 68 Lumenal. {ECO:0000269|PubMed:26280335, FT ECO:0000305|PubMed:14593096}. FT TRANSMEM 69 89 Helical; Name=3. FT {ECO:0000269|PubMed:26280335}. FT TOPO_DOM 90 118 Cytoplasmic. FT {ECO:0000269|PubMed:26280335, FT ECO:0000305|PubMed:14593096}. FT TRANSMEM 119 139 Helical; Name=4. FT {ECO:0000269|PubMed:26280335}. FT TOPO_DOM 140 158 Lumenal. {ECO:0000269|PubMed:26280335, FT ECO:0000305|PubMed:14593096}. FT TRANSMEM 159 179 Helical; Name=5. FT {ECO:0000269|PubMed:26280335}. FT TOPO_DOM 180 186 Cytoplasmic. FT {ECO:0000269|PubMed:26280335, FT ECO:0000305|PubMed:14593096}. FT TRANSMEM 187 207 Helical; Name=6. FT {ECO:0000269|PubMed:26280335}. FT TOPO_DOM 208 213 Lumenal. {ECO:0000269|PubMed:26280335, FT ECO:0000305|PubMed:14593096}. FT TRANSMEM 214 234 Helical; Name=7. FT {ECO:0000269|PubMed:26280335}. FT TOPO_DOM 235 265 Cytoplasmic. FT {ECO:0000269|PubMed:26280335, FT ECO:0000305|PubMed:14593096}. FT VAR_SEQ 39 120 AFFWLVSLLLASVVWFILVHVTDRSDARLQYGLLIFGAAVS FT VLLQEVFRFAYYKLLKKADEGLASLSEDGRSPISIRQMAYV FT -> RCSALPTTSCLI (in isoform 3). FT {ECO:0000303|PubMed:14702039}. FT /FTId=VSP_045424. FT VAR_SEQ 246 247 RR -> KD (in isoform 2). FT {ECO:0000303|PubMed:10810093, FT ECO:0000303|PubMed:12975309, FT ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334, FT ECO:0000303|Ref.2}. FT /FTId=VSP_008355. FT VAR_SEQ 248 265 Missing (in isoform 2). FT {ECO:0000303|PubMed:10810093, FT ECO:0000303|PubMed:12975309, FT ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334, FT ECO:0000303|Ref.2}. FT /FTId=VSP_008356. FT MUTAGEN 171 171 H->A: Impaired gamma-secretease assembly FT and reduced proteolytic activity of the FT gamma-secretase complex. FT {ECO:0000269|PubMed:19369254}. FT MUTAGEN 197 197 H->A: Impaired gamma-secretease assembly FT and reduced proteolytic activity of the FT gamma-secretase complex. FT {ECO:0000269|PubMed:19369254}. FT CONFLICT 236 236 L -> I (in Ref. 8; AAH01230). FT {ECO:0000305}. FT HELIX 3 13 {ECO:0000244|PDB:6IYC}. FT HELIX 15 23 {ECO:0000244|PDB:6IYC}. FT TURN 24 27 {ECO:0000244|PDB:6IYC}. FT HELIX 31 60 {ECO:0000244|PDB:6IYC}. FT HELIX 66 102 {ECO:0000244|PDB:6IYC}. FT STRAND 104 108 {ECO:0000244|PDB:6IYC}. FT HELIX 114 134 {ECO:0000244|PDB:6IYC}. FT TURN 135 139 {ECO:0000244|PDB:6IYC}. FT HELIX 140 142 {ECO:0000244|PDB:6IYC}. FT HELIX 156 184 {ECO:0000244|PDB:6IYC}. FT HELIX 189 202 {ECO:0000244|PDB:6IYC}. FT HELIX 203 206 {ECO:0000244|PDB:6IYC}. FT HELIX 210 212 {ECO:0000244|PDB:6IYC}. FT HELIX 215 231 {ECO:0000244|PDB:6IYC}. FT HELIX 236 240 {ECO:0000244|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 //