Protein-coding gene in the species Homo sapiens
GSAP |
---|
|
Identifiers |
---|
Aliases | GSAP, PION, Protein pigeon homolog, gamma-secretase activating protein |
---|
External IDs | OMIM: 613552; MGI: 2442259; HomoloGene: 45504; GeneCards: GSAP; OMA:GSAP - orthologs |
---|
Gene location (Human) |
---|
| Chr. | Chromosome 7 (human)[1] |
---|
| Band | 7q11.23 | Start | 77,310,751 bp[1] |
---|
End | 77,416,349 bp[1] |
---|
|
Gene location (Mouse) |
---|
| Chr. | Chromosome 5 (mouse)[2] |
---|
| Band | 5|5 A3 | Start | 21,391,253 bp[2] |
---|
End | 21,520,130 bp[2] |
---|
|
RNA expression pattern |
---|
Bgee | Human | Mouse (ortholog) |
---|
Top expressed in | - granulocyte
- right uterine tube
- monocyte
- spleen
- right lung
- epithelium of nasopharynx
- visceral pleura
- right lobe of thyroid gland
- secondary oocyte
- upper lobe of left lung
|
| Top expressed in | - lumbar spinal ganglion
- granulocyte
- right lung
- spermatid
- right lung lobe
- right kidney
- Rostral migratory stream
- left lobe of liver
- tibiofemoral joint
- proximal tubule
|
| More reference expression data |
|
---|
BioGPS | |
---|
|
Gene ontology |
---|
Molecular function | - amyloid-beta binding
- protein binding
| Cellular component | - trans-Golgi network
- Golgi apparatus
| Biological process | - regulation of proteolysis
- positive regulation of amyloid-beta formation
| Sources:Amigo / QuickGO |
|
Orthologs |
---|
Species | Human | Mouse |
---|
Entrez | | |
---|
Ensembl | | |
---|
UniProt | | |
---|
RefSeq (mRNA) | NM_017439 NM_001350896 NM_001350897 NM_001350898 NM_001350899
|
---|
NM_001350900 NM_001350901 |
| |
---|
NM_175437 NM_001359876 NM_001359877 |
|
---|
RefSeq (protein) | NP_059135 NP_001337825 NP_001337826 NP_001337827 NP_001337828
|
---|
NP_001337829 NP_001337830 |
| |
---|
NP_780646 NP_001346805 NP_001346806 |
|
---|
Location (UCSC) | Chr 7: 77.31 – 77.42 Mb | Chr 5: 21.39 – 21.52 Mb |
---|
PubMed search | [3] | [4] |
---|
|
Wikidata |
View/Edit Human | View/Edit Mouse |
|
Protein pigeon homolog also known as gamma-secretase activating protein (GSAP) is a protein that in humans is encoded by the PION gene.[5]
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.[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.
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 |
---|
Search for |
---|
Structures | Swiss-model |
---|
Domains | InterPro |
---|
| |
Protein
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]
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).[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 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[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]
Discovery
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]
References
- ^ 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
- 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.