APH1A_HUMAN
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 03-AUG-2022, entry version 178.
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; 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};
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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 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; Q96BI3; -.
DR SMR; Q96BI3; -.
DR BioGRID; 119296; 59.
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 TCDB; 1.A.121.1.2; the anterior pharynx-defective water channel (aph-wc) family.
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 Antibodypedia; 34020; 364 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 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; FFNAFDT; -.
DR OrthoDB; 1085102at2759; -.
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; 13 hits in 1076 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 195 other tissues.
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-UCL.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IC: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; 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: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: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; PTHR12889; 1.
DR Pfam; PF06105; Aph-1; 1.
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
