GSAP_HUMAN
ID GSAP_HUMAN Reviewed; 854 AA.
AC A4D1B5; A4D1B6; Q3MJC0; Q8ND73; Q9UMH3; Q9Y4L9;
DT 20-MAY-2008, integrated into UniProtKB/Swiss-Prot.
DT 20-MAY-2008, sequence version 2.
DT 03-AUG-2022, entry version 105.
DE RecName: Full=Gamma-secretase-activating protein;
DE Short=GSAP;
DE AltName: Full=Protein pigeon homolog;
DE Contains:
DE RecName: Full=Gamma-secretase-activating protein 16 kDa C-terminal form;
DE Short=GSAP-16K;
GN Name=GSAP; Synonyms=PION;
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 [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K.,
RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A.,
RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H.,
RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A.,
RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P.,
RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M.,
RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S.,
RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R.,
RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J.,
RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W.,
RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A.,
RA Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E.,
RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A.,
RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A.,
RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R.,
RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H.,
RA Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT ARG-47.
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D.,
RA Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S.,
RA Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R.,
RA Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N.,
RA Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E.,
RA Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R.,
RA Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T.,
RA Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W.,
RA Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A.,
RA Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X.,
RA Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E.,
RA Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J.,
RA Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [3]
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Brain;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 36-854 (ISOFORM 3).
RC TISSUE=Lymph node;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 587-854.
RG The European IMAGE consortium;
RL Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, IDENTIFICATION BY MASS SPECTROMETRY,
RP PROTEOLYTIC PROCESSING, IMATINIB-BINDING, TISSUE SPECIFICITY, AND
RP INTERACTION WITH APP AND THE GAMMA-SECRETASE COMPLEX.
RX PubMed=20811458; DOI=10.1038/nature09325;
RA He G., Luo W., Li P., Remmers C., Netzer W.J., Hendrick J., Bettayeb K.,
RA Flajolet M., Gorelick F., Wennogle L.P., Greengard P.;
RT "Gamma-secretase activating protein is a therapeutic target for Alzheimer's
RT disease.";
RL Nature 467:95-98(2010).
CC -!- FUNCTION: Regulator of gamma-secretase activity, which specifically
CC activates the production of amyloid-beta protein (amyloid-beta protein
CC 40 and amyloid-beta protein 42), without affecting the cleavage of
CC other gamma-secretase targets such has Notch. The gamma-secretase
CC complex is an endoprotease complex that catalyzes the intramembrane
CC cleavage of integral membrane proteins such as Notch receptors and APP
CC (amyloid-beta precursor protein). Specifically promotes the gamma-
CC cleavage of APP CTF-alpha (also named APP-CTF) by the gamma-secretase
CC complex to generate amyloid-beta, while it reduces the epsilon-cleavage
CC of APP CTF-alpha, leading to a low production of AICD.
CC {ECO:0000269|PubMed:20811458}.
CC -!- SUBUNIT: Interacts with APP; specifically interacts with the CTF-alpha
CC product of APP. Interacts with the gamma-secretase complex.
CC {ECO:0000269|PubMed:20811458}.
CC -!- INTERACTION:
CC A4D1B5; P05067: APP; NbExp=3; IntAct=EBI-15875313, EBI-77613;
CC -!- SUBCELLULAR LOCATION: Golgi apparatus, trans-Golgi network
CC {ECO:0000269|PubMed:20811458}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=A4D1B5-1; Sequence=Displayed;
CC Name=2;
CC IsoId=A4D1B5-2; Sequence=VSP_033772, VSP_033773, VSP_033774;
CC Name=3;
CC IsoId=A4D1B5-3; Sequence=VSP_033773, VSP_033774;
CC Name=4;
CC IsoId=A4D1B5-4; Sequence=VSP_033771;
CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:20811458}.
CC -!- PTM: The protein is first synthesized as a holoprotein form of 98 kDa
CC and rapidly processed into the gamma-secretase-activating protein 16
CC kDa C-terminal form, which constitutes the predominant form.
CC {ECO:0000269|PubMed:20811458}.
CC -!- MISCELLANEOUS: The gamma-secretase regulator activity is specifically
CC inhibited by imatinib (also known as STI571 or Gleevec), an anticancer
CC drug that selectively decreases amyloid-beta protein production.
CC Imatinib binds PION/GSAP and acts by preventing PION/GSAP interaction
CC with the gamma-secretase substrate, CTF-alpha (PubMed:20811458).
CC {ECO:0000305|PubMed:20811458}.
CC -!- MISCELLANEOUS: Its role as an activator of amyloid-beta protein
CC production makes it a promising therapeutic target for the treatment of
CC Alzheimer disease. {ECO:0000305|PubMed:20811458}.
CC -!- SIMILARITY: Belongs to the GSAP family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAD39023.2; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AC004921; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC073635; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH236949; EAL24199.1; -; Genomic_DNA.
DR EMBL; CH236949; EAL24200.1; -; Genomic_DNA.
DR EMBL; CH471091; EAW77039.1; -; Genomic_DNA.
DR EMBL; BC101499; AAI01500.2; -; mRNA.
DR EMBL; AL834358; CAD39023.2; ALT_INIT; mRNA.
DR EMBL; AL079277; CAB45152.1; -; mRNA.
DR EMBL; AL079297; CAB45193.1; -; mRNA.
DR CCDS; CCDS34672.2; -. [A4D1B5-1]
DR RefSeq; NP_059135.2; NM_017439.3. [A4D1B5-1]
DR AlphaFoldDB; A4D1B5; -.
DR BioGRID; 119901; 5.
DR DIP; DIP-59240N; -.
DR IntAct; A4D1B5; 2.
DR STRING; 9606.ENSP00000257626; -.
DR BindingDB; A4D1B5; -.
DR ChEMBL; CHEMBL3638343; -.
DR iPTMnet; A4D1B5; -.
DR PhosphoSitePlus; A4D1B5; -.
DR BioMuta; GSAP; -.
DR EPD; A4D1B5; -.
DR MassIVE; A4D1B5; -.
DR MaxQB; A4D1B5; -.
DR PaxDb; A4D1B5; -.
DR PeptideAtlas; A4D1B5; -.
DR PRIDE; A4D1B5; -.
DR TopDownProteomics; A4D1B5-1; -. [A4D1B5-1]
DR Antibodypedia; 15032; 193 antibodies from 21 providers.
DR DNASU; 54103; -.
DR Ensembl; ENST00000257626.12; ENSP00000257626.7; ENSG00000186088.16. [A4D1B5-1]
DR GeneID; 54103; -.
DR KEGG; hsa:54103; -.
DR MANE-Select; ENST00000257626.12; ENSP00000257626.7; NM_017439.4; NP_059135.2.
DR UCSC; uc003ugf.3; human. [A4D1B5-1]
DR CTD; 54103; -.
DR DisGeNET; 54103; -.
DR GeneCards; GSAP; -.
DR HGNC; HGNC:28042; GSAP.
DR HPA; ENSG00000186088; Low tissue specificity.
DR MIM; 613552; gene.
DR neXtProt; NX_A4D1B5; -.
DR OpenTargets; ENSG00000186088; -.
DR PharmGKB; PA164724500; -.
DR VEuPathDB; HostDB:ENSG00000186088; -.
DR eggNOG; ENOG502QWQK; Eukaryota.
DR GeneTree; ENSGT00390000012875; -.
DR HOGENOM; CLU_008601_0_0_1; -.
DR InParanoid; A4D1B5; -.
DR OMA; CANQSRN; -.
DR OrthoDB; 1035231at2759; -.
DR PhylomeDB; A4D1B5; -.
DR TreeFam; TF323853; -.
DR PathwayCommons; A4D1B5; -.
DR SignaLink; A4D1B5; -.
DR BioGRID-ORCS; 54103; 8 hits in 1063 CRISPR screens.
DR ChiTaRS; GSAP; human.
DR GeneWiki; Protein_pigeon_homolog; -.
DR GenomeRNAi; 54103; -.
DR Pharos; A4D1B5; Tchem.
DR PRO; PR:A4D1B5; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; A4D1B5; protein.
DR Bgee; ENSG00000186088; Expressed in granulocyte and 190 other tissues.
DR ExpressionAtlas; A4D1B5; baseline and differential.
DR Genevisible; A4D1B5; HS.
DR GO; GO:0005802; C:trans-Golgi network; IDA:UniProtKB.
DR GO; GO:0001540; F:amyloid-beta binding; IDA:UniProtKB.
DR GO; GO:1902004; P:positive regulation of amyloid-beta formation; IDA:UniProtKB.
DR GO; GO:0030162; P:regulation of proteolysis; IDA:UniProtKB.
DR InterPro; IPR028010; GSAP_C_dom.
DR InterPro; IPR026172; GSAP_fam.
DR PANTHER; PTHR13630; PTHR13630; 1.
DR Pfam; PF14959; GSAP-16; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Golgi apparatus; Reference proteome.
FT CHAIN 1..854
FT /note="Gamma-secretase-activating protein"
FT /id="PRO_0000335809"
FT CHAIN 734..854
FT /note="Gamma-secretase-activating protein 16 kDa C-terminal
FT form"
FT /evidence="ECO:0000255"
FT /id="PRO_0000403728"
FT VAR_SEQ 1..606
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_033771"
FT VAR_SEQ 446
FT /note="Q -> QWRQRADLNTNRVLSDFLK (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_033772"
FT VAR_SEQ 559
FT /note="K -> V (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:17974005"
FT /id="VSP_033773"
FT VAR_SEQ 560..854
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:17974005"
FT /id="VSP_033774"
FT VARIANT 47
FT /note="H -> R (in dbSNP:rs6949654)"
FT /evidence="ECO:0000269|PubMed:12690205"
FT /id="VAR_043467"
FT VARIANT 305
FT /note="G -> E (in dbSNP:rs1527263)"
FT /id="VAR_043468"
FT VARIANT 649
FT /note="V -> I (in dbSNP:rs17151692)"
FT /id="VAR_043469"
FT VARIANT 653
FT /note="W -> L (in dbSNP:rs17151689)"
FT /id="VAR_043470"
SQ SEQUENCE 854 AA; 97802 MW; D7B4A3A95E2E8C3B CRC64;
MALRLVADFD LGKDVLPWLR AQRAVSEASG AGSGGADVLE NDYESLHVLN VERNGNIIYT
YKDDKGNVVF GLYDCQTRQN ELLYTFEKDL QVFSCSVNSE RTLLAASLVQ STKEGKRNEL
QPGSKCLTLL VEIHPVNNVK VLKAVDSYIW VQFLYPHIES HPLPENHLLL ISEEKYIEQF
RIHVAQEDGN RVVIKNSGHL PRDRIAEDFV WAQWDMSEQR LYYIDLKKSR SILKCIQFYA
DESYNLMFEV PLDISLSNSG FKLVNFGCDY HQYRDKFSKH LTLCVFTNHT GSLCVCYSPK
CASWGQITYS VFYIHKGHSK TFTTSLENVG SHMTKGITFL NLDYYVAVYL PGHFFHLLNV
QHPDLICHNL FLTGNNEMID MLPHCPLQSL SGSLVLDCCS GKLYRALLSQ SSLLQLLQNT
CLDCEKMAAL HCALYCGQGA QFLEAQIIQW ISENVSACHS FDLIQEFIIA SSYWSVYSET
SNMDKLLPHS SVLTWNTEIP GITLVTEDIA LPLMKVLSFK GYWEKLNSNL EYVKYAKPHF
HYNNSVVRRE WHNLISEEKT GKRRSAAYVR NILDNAVKVI SNLEARNLGP RLTPLLQEED
SHQRLLMGLM VSELKDHFLR HLQGVEKKKI EQMVLDYISK LLDLICHIVE TNWRKHNLHS
WVLHFNSRGS AAEFAVFHIM TRILEATNSL FLPLPPGFHT LHTILGVQCL PLHNLLHCID
SGVLLLTETA VIRLMKDLDN TEKNEKLKFS IIVRLPPLIG QKICRLWDHP MSSNIISRNH
VTRLLQNYKK QPRNSMINKS SFSVEFLPLN YFIEILTDIE SSNQALYPFE GHDNVDAEFV
EEAALKHTAM LLGL
