The human PION gene is located on the long (q) arm of chromosome 7 at band 11.23, from base pair 76,778,007 to base pair 76,883,653.[6] Highly conserved PIONorthologs have been identified in most vertebrates for which complete genome data are available.[7] More distantly related orthologs are also expressed in insects including the pigeon gene in Drosophila melanogaster that when mutated produces the "pigeon" phenotype. The name of the human PION gene derives the corresponding Drosophila gene.
The transcribed human pigeon homolog protein is 854 amino acid residues in length.[8] A 16 kDa fragment (GSAP-16K) derived from 121 residues from the C-terminus region of the full length protein is known as the γ-secretase activating protein (GSAP).[9]
Functionedit
γ-secretase activating protein (GSAP) increases β-amyloid production through a mechanism involving its interactions with both γ-secretase and its substrate, the amyloid precursor protein (APP).[9] By binding to both the γ-secretase enzyme and its APP substrate, GSAP increases the affinity and the selectivity of the enzyme for this particular substrate.
Therapeutic target for Alzheimer's diseaseedit
The activating function of GSAP can be inhibited by the anticancer drug imatinib (Gleevec) which in turn prevents γ-secretase from converting APP into plaque forming β-amyloid without affecting the other functions of γ-secretase. Imatinib itself does not get into the brain[10] so imatinib could not be used as an AD therapeutic. However it may be possible to identify imatinib-like drugs that do get into the brain. Hence GSAP represents a potential therapeutic target for the treatment of Alzheimer's disease (AD).[9]
The drug semagacestat in contrast to imatinib, works by directly inhibiting the γ-secretase. While semagacestat reduces β-amyloid plaque formation in AD patients, γ-secretase is also needed to make other important proteins.[11] The failure of semagacestat to improve the cognitive function of AD patients may be due to its non-selective blockade of γ-secretase. The more selective blockade of γ-secretase provided by inhibiting GSAP may make GSAP a more efficacious and safer drug target than γ-secretase.[9]
Discoveryedit
The PION gene was originally discovered through a large scale genome sequencing effort.[12] However the function of the PION gene product remained a mystery. In the laboratory of Paul Greengard, a screen of compounds that could inhibit the formation of β-amyloid identified imatinib,[13] however it was not immediately known how it accomplished this. Later it was discovered by Greengard's lab that imatinib inhibited the function of GSAP and that GSAP in turn functions as an activator of γ-secretase.[9]
Referencesedit
^ abcGRCh38: Ensembl release 89: ENSG00000186088 - Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000039934 - Ensembl, May 2017
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ abcdeHe G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, Bettayeb K, Flajolet M, Gorelick F, Wennogle LP, Greengard P (September 2010). "Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease". Nature. 467 (7311): 95–8. Bibcode:2010Natur.467...95H. doi:10.1038/nature09325. PMC2936959. PMID 20811458.
Gina Kolata (September 1, 2010). "Finding Suggests New Aim for Alzheimer's Drugs". The New York Times.
^Dai H, Marbach P, Lemaire M, Hayes M, Elmquist WF (March 2003). "Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux". The Journal of Pharmacology and Experimental Therapeutics. 304 (3): 1085–92. doi:10.1124/jpet.102.045260. PMID 12604685. S2CID 15871348.
^Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, et al. (December 2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proceedings of the National Academy of Sciences of the United States of America. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC139241. PMID 12477932.
^Netzer WJ, Dou F, Cai D, Veach D, Jean S, Li Y, Bornmann WG, Clarkson B, Xu H, Greengard P (October 2003). "Gleevec inhibits beta-amyloid production but not Notch cleavage". Proceedings of the National Academy of Sciences of the United States of America. 100 (21): 12444–9. Bibcode:2003PNAS..10012444N. doi:10.1073/pnas.1534745100. PMC218777. PMID 14523244.
Further readingedit
Oh JH, Yang JO, Hahn Y, Kim MR, Byun SS, Jeon YJ, Kim JM, Song KS, Noh SM, Kim S, Yoo HS, Kim YS, Kim NS (December 2005). "Transcriptome analysis of human gastric cancer". Mammalian Genome. 16 (12): 942–54. doi:10.1007/s00335-005-0075-2. PMID 16341674. S2CID 69278.
April 15, 2024
protein, pigeon, homolog, also, known, gamma, secretase, activating, protein, gsap, protein, that, humans, encoded, pion, gene, gsapidentifiersaliasesgsap, pion, gamma, secretase, activating, proteinexternal, idsomim, 613552, 2442259, homologene, 45504, geneca. Protein pigeon homolog also known as gamma secretase activating protein GSAP is a protein that in humans is encoded by the PION gene 5 GSAPIdentifiersAliasesGSAP PION Protein pigeon homolog gamma secretase activating proteinExternal IDsOMIM 613552 MGI 2442259 HomoloGene 45504 GeneCards GSAPGene location Human Chr Chromosome 7 human 1 Band7q11 23Start77 310 751 bp 1 End77 416 349 bp 1 Gene location Mouse Chr Chromosome 5 mouse 2 Band5 5 A3Start21 391 253 bp 2 End21 520 130 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inright uterine tubemonocytespleenright lungvisceral pleuraright lobe of thyroid glandsecondary oocyteupper lobe of left lungleft lobe of thyroid glandappendixTop expressed inright lungspermatidright lung lobeleft lobe of liverproximal tubulespleencarotid bodyleft lung lobebloodolfactory bulbMore reference expression dataBioGPSn aGene ontologyMolecular functionamyloid beta binding protein bindingCellular componenttrans Golgi network Golgi apparatusBiological processregulation of proteolysis positive regulation of amyloid beta formationSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez54103212167EnsemblENSG00000186088ENSMUSG00000039934UniProtA4D1B5Q3TCV3RefSeq mRNA NM 017439NM 001350896NM 001350897NM 001350898NM 001350899NM 001350900NM 001350901NM 175437NM 001359876NM 001359877RefSeq protein NP 059135NP 001337825NP 001337826NP 001337827NP 001337828NP 001337829NP 001337830NP 780646NP 001346805NP 001346806Location UCSC Chr 7 77 31 77 42 MbChr 5 21 39 21 52 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse PION redirects here For other uses see Pion disambiguation Contents 1 Gene 2 Protein 3 Function 4 Therapeutic target for Alzheimer s disease 5 Discovery 6 References 7 Further readingGene editThe human PION gene is located on the long q arm of chromosome 7 at band 11 23 from base pair 76 778 007 to base pair 76 883 653 6 Highly conserved PION orthologs have been identified in most vertebrates for which complete genome data are available 7 More distantly related orthologs are also expressed in insects including the pigeon gene in Drosophila melanogaster that when mutated produces the pigeon phenotype The name of the human PION gene derives the corresponding Drosophila gene pigeonIdentifiersOrganismDrosophila melanogasterSymbolPigeonAlt symbolsProtein linotteEntrez35200RefSeq mRNA NM 057598RefSeq Prot NP 476946UniProtQ24118Other dataChromosome2L 19 19 19 19 MbSearch forStructuresSwiss modelDomainsInterProProtein editThe transcribed human pigeon homolog protein is 854 amino acid residues in length 8 A 16 kDa fragment GSAP 16K derived from 121 residues from the C terminus region of the full length protein is known as the g secretase activating protein GSAP 9 Function editg secretase activating protein GSAP increases b amyloid production through a mechanism involving its interactions with both g secretase and its substrate the amyloid precursor protein APP 9 By binding to both the g secretase enzyme and its APP substrate GSAP increases the affinity and the selectivity of the enzyme for this particular substrate Therapeutic target for Alzheimer s disease editThe activating function of GSAP can be inhibited by the anticancer drug imatinib Gleevec which in turn prevents g secretase from converting APP into plaque forming b amyloid without affecting the other functions of g secretase Imatinib itself does not get into the brain 10 so imatinib could not be used as an AD therapeutic However it may be possible to identify imatinib like drugs that do get into the brain Hence GSAP represents a potential therapeutic target for the treatment of Alzheimer s disease AD 9 The drug semagacestat in contrast to imatinib works by directly inhibiting the g secretase While semagacestat reduces b amyloid plaque formation in AD patients g secretase is also needed to make other important proteins 11 The failure of semagacestat to improve the cognitive function of AD patients may be due to its non selective blockade of g secretase The more selective blockade of g secretase provided by inhibiting GSAP may make GSAP a more efficacious and safer drug target than g secretase 9 Discovery editThe PION gene was originally discovered through a large scale genome sequencing effort 12 However the function of the PION gene product remained a mystery In the laboratory of Paul Greengard a screen of compounds that could inhibit the formation of b amyloid identified imatinib 13 however it was not immediately known how it accomplished this Later it was discovered by Greengard s lab that imatinib inhibited the function of GSAP and that GSAP in turn functions as an activator of g secretase 9 References edit a b c GRCh38 Ensembl release 89 ENSG00000186088 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000039934 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Entrez Gene pigeon homolog Drosophila Human chr7 76778007 76883653 UCSC Genome Browser HomoloGene 45504 UniProt A4D1B5 a b c d e He G Luo W Li P Remmers C Netzer WJ Hendrick J Bettayeb K Flajolet M Gorelick F Wennogle LP Greengard P September 2010 Gamma secretase activating protein is a therapeutic target for Alzheimer s disease Nature 467 7311 95 8 Bibcode 2010Natur 467 95H doi 10 1038 nature09325 PMC 2936959 PMID 20811458 Gina Kolata September 1 2010 Finding Suggests New Aim for Alzheimer s Drugs The New York Times Dai H Marbach P Lemaire M Hayes M Elmquist WF March 2003 Distribution of STI 571 to the brain is limited by P glycoprotein mediated efflux The Journal of Pharmacology and Experimental Therapeutics 304 3 1085 92 doi 10 1124 jpet 102 045260 PMID 12604685 S2CID 15871348 St George Hyslop P Schmitt Ulms G September 2010 Alzheimer s disease Selectively tuning gamma secretase Nature 467 7311 36 7 Bibcode 2010Natur 467 36S doi 10 1038 467036a PMID 20811445 S2CID 13792782 Strausberg RL Feingold EA Grouse LH Derge JG Klausner RD Collins FS et al December 2002 Generation and initial analysis of more than 15 000 full length human and mouse cDNA sequences Proceedings of the National Academy of Sciences of the United States of America 99 26 16899 903 Bibcode 2002PNAS 9916899M doi 10 1073 pnas 242603899 PMC 139241 PMID 12477932 Netzer WJ Dou F Cai D Veach D Jean S Li Y Bornmann WG Clarkson B Xu H Greengard P October 2003 Gleevec inhibits beta amyloid production but not Notch cleavage Proceedings of the National Academy of Sciences of the United States of America 100 21 12444 9 Bibcode 2003PNAS 10012444N doi 10 1073 pnas 1534745100 PMC 218777 PMID 14523244 Further reading editOh JH Yang JO Hahn Y Kim MR Byun SS Jeon YJ Kim JM Song KS Noh SM Kim S Yoo HS Kim YS Kim NS December 2005 Transcriptome analysis of human gastric cancer Mammalian Genome 16 12 942 54 doi 10 1007 s00335 005 0075 2 PMID 16341674 S2CID 69278 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