Protein pigeon homolog

Gamma-secretase activating protein
Identifiers
Symbols GSAP ; PION
External IDs OMIM: 613552 MGI: 2442259 HomoloGene: 45504 GeneCards: GSAP Gene
Orthologs
Species Human Mouse
Entrez 54103 212167
Ensembl ENSG00000186088 ENSMUSG00000039934
UniProt A4D1B5 Q3TCV3
RefSeq (mRNA) NM_017439 NM_175437
RefSeq (protein) NP_059135 NP_780646
Location (UCSC) Chr 7:
77.31 – 77.42 Mb		 Chr 5:
21.19 – 21.32 Mb
PubMed search

Protein pigeon homolog also known as gamma-secretase activating protein (GSAP) is a protein that in humans is encoded by the PION gene.[1]

Gene

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.[2] Highly conserved PION orthologs have been identified in most vertebrates for which complete genome data are available.[3] 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.

pigeon
Identifiers
Organism Drosophila melanogaster
Symbol Pigeon
Alt. symbols Protein linotte
Entrez 35200
RefSeq (mRNA) NM_057598
RefSeq (Prot) NP_476946
UniProt Q24118
Other data
Chromosome 2L: 19.19 - 19.19 Mb

Protein

The transcribed human pigeon homolog protein is 854 amino acid residues in length.[4] 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).[5]

Function

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).[5] 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 disease

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[6] 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).[5]

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.[7] 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.[5]

Discovery

The PION gene was originally discovered through a large scale genome sequencing effort.[8] 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,[9] 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.[5]

References

  1. ↑ "Entrez Gene: pigeon homolog (Drosophila)".
  2. ↑ "Human chr7:76778007-76883653". UCSC Genome Browser.
  3. ↑ HomoloGene: 45504
  4. ↑ UniProt: A4D1B5
  5. 1 2 3 4 5 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): 95–98. doi:10.1038/nature09325. PMC 2936959. PMID 20811458. Lay summary – New York Times.
  6. ↑ 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". J. Pharmacol. Exp. Ther. 304 (3): 1085–92. doi:10.1124/jpet.102.045260. PMID 12604685.
  7. ↑ St George-Hyslop P, Schmitt-Ulms G (September 2010). "Alzheimer's disease: Selectively tuning gamma-secretase". Nature 467 (7311): 36–7. doi:10.1038/467036a. PMID 20811445.
  8. ↑ Strausberg RL, Feingold EA, Grouse LH, et al. (December 2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
  9. ↑ 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". Proc. Natl. Acad. Sci. U.S.A. 100 (21): 12444–9. doi:10.1073/pnas.1534745100. PMC 218777. PMID 14523244.

Further reading

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