CPA3

Carboxypeptidase A3 (mast cell carboxypeptidase A), also known as CPA3, is an enzyme which in humans is encoded by the CPA3 gene.^[5][6] The "CPA3" gene expression has only been detected in mast cells and mast-cell-like lines, and CPA3 is located in secretory granules. CPA3 is one of 8-9 members of the A/B subfamily that includes the well-studied pancreatic enzymes carboxypeptidase A1 (CPA1), carboxypeptidase A2 (CPA2), and carboxypeptidase B. This subfamily includes 6 carboxypeptidase A-like enzymes, numbered 1-6. The enzyme now called CPA3 was originally named mast cell carboxypeptidase A, and another protein was initially called CPA3.^[7] A gene nomenclature committee renamed mast cell carboxypeptidase A as CPA3, and the original CPA3 reported by Huang et al. became CPA4 to reflect the order of their discovery.

CPA3
Identifiers
Aliases	CPA3, MC-CPA, carboxypeptidase A3
External IDs	OMIM: 114851; MGI: 88479; HomoloGene: 122138; GeneCards: CPA3; OMA:CPA3 - orthologs
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3q24 Start 148,865,296 bp[1] End 148,897,203 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3 A2|3 6.25 cM Start 20,269,784 bp[2] End 20,296,345 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gallbladder skin of hip skin of thigh rectum visceral pleura right lung mucosa of ileum upper lobe of left lung right coronary artery lower lobe of lung Top expressed in dermis umbilical cord tunica adventitia of aorta skin of abdomen skin of external ear ankle vas deferens skin of back lip human fetus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function metal ion binding carboxypeptidase activity zinc ion binding peptidase activity hydrolase activity metallopeptidase activity metallocarboxypeptidase activity Cellular component transport vesicle secretory granule cytoplasmic vesicle extracellular space extracellular matrix extracellular region collagen-containing extracellular matrix Biological process regulation of angiotensin levels in blood angiotensin maturation proteolysis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1359 12873 Ensembl ENSG00000163751 ENSMUSG00000001865 UniProt P15088 P15089 RefSeq (mRNA) NM_001870 NM_007753 RefSeq (protein) NP_001861 NP_031779 Location (UCSC) Chr 3: 148.87 – 148.9 Mb Chr 3: 20.27 – 20.3 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

Gene

The "CPA3" gene is a 32kb-gene located at chromosome 3q24, consisting of 11 exons.

Protein

CPA3 shares significant homology with the CPA subfamily of metalloprecarboxypeptidases and all the residues essential for the coordination of the Zn²⁺ active site, substrate peptide anchoring, and CP activity are preserved in the putative CPA3 protein. It resembles pancreatic CPA1 in cleaving C-terminal aromatic and aliphatic amino acid residues.CPA3 contains an N-terminal sequence of 16 amino acids and a pro-peptide between the NH2-terminal signal peptide sequence and COOH-terminal CP moiety.^[8][7]

Function

CPA3 has a pH optimum in the neutral to basic range. CPA3 functions together with endopeptidases secreted from mast cells such as chymases and tryptases to degrade proteins and peptides, including the apolipoprotein B component of LDL particles and angiotensin I.^[9][10] Upon mast cell activation and degranulation, CPA3, the chymases, and tryptases are released in complexes with heparin proteoglycan. The parasitic nematode Ascaris produces CPA3 inhibitors, which increase its survival during infection. This finding implies that CPA3 might be involved in host defense against certain parasites.^[11] CPA3 is also reported to have an important role in the protection towards snake venom toxins and vasoconstricting peptide endothelin 1(ET1).^[12][13]

Clinical significance

CPA3 provides protection from ET-1-induced damage, suggesting CPA3 could have a role in regulating sepsis. The involvement of CPA3 in autoimmune disease models makes it a potential diagnostic parameter of related diseases.^[14] The significantly increased concentration of CPA3 in drug-induced anaphylaxis also implies that CPA3 could serve as a diagnostic parameter and detection of it could improve the forensic identification.^[15] A new mast cell subtype reported to appear in mucosa is implicated in allergic inflammation and these mast cells have high levels of CPA3. The highly upregulated transcript of CPA3 is readily detected in luminal brushings and biopsies, making it a useful biomarker of allergic inflammation.^[16][17]

Interactions

CPA3 has been known to interact with:

• Heparin^[18]
• PCI^[19]
• SR48692^[20]
• Tissue carboxypeptidase inhibitor^[21]
• Neurotensin^[22]

References

1. GRCh38: Ensembl release 89: ENSG00000163751 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000001865 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. [0.0https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1359 "Entrez Gene: CPA3 carboxypeptidase A3 (mast cell)"]. {{cite web}}: Check |url= value (help)
6. Reynolds DS, Gurley DS, Austen KF (January 1992). "Cloning and characterization of the novel gene for mast cell carboxypeptidase A". The Journal of Clinical Investigation. 89 (1): 273–82. doi:10.1172/JCI115571. PMC 442845. PMID 1729276.
7. Huang H, Reed CP, Zhang JS, Shridhar V, Wang L, Smith DI (June 1999). "Carboxypeptidase A3 (CPA3): a novel gene highly induced by histone deacetylase inhibitors during differentiation of prostate epithelial cancer cells". Cancer Research. 59 (12): 2981–8. PMID 10383164.
8. von Heijne G (July 1985). "Signal sequences. The limits of variation". Journal of Molecular Biology. 184 (1): 99–105. doi:10.1016/0022-2836(85)90046-4. PMID 4032478.
9. Kokkonen JO, Vartiainen M, Kovanen PT (December 1986). "Low density lipoprotein degradation by secretory granules of rat mast cells. Sequential degradation of apolipoprotein B by granule chymase and carboxypeptidase A". The Journal of Biological Chemistry. 261 (34): 16067–72. doi:10.1016/S0021-9258(18)66677-3. PMID 3536921.
10. Lundequist A, Tchougounova E, Abrink M, Pejler G (July 2004). "Cooperation between mast cell carboxypeptidase A and the chymase mouse mast cell protease 4 in the formation and degradation of angiotensin II". The Journal of Biological Chemistry. 279 (31): 32339–44. doi:10.1074/jbc.M405576200. PMID 15173164.
11. Sanglas L, Aviles FX, Huber R, Gomis-Rüth FX, Arolas JL (February 2009). "Mammalian metallopeptidase inhibition at the defense barrier of Ascaris parasite". Proceedings of the National Academy of Sciences of the United States of America. 106 (6): 1743–7. Bibcode:2009PNAS..106.1743S. doi:10.1073/pnas.0812623106. PMC 2644108. PMID 19179285.
12. Metz M, Piliponsky AM, Chen CC, Lammel V, Abrink M, Pejler G, Tsai M, Galli SJ (July 2006). "Mast cells can enhance resistance to snake and honeybee venoms". Science. 313 (5786): 526–30. Bibcode:2006Sci...313..526M. doi:10.1126/science.1128877. PMID 16873664. S2CID 30725308.
13. Maurer M, Wedemeyer J, Metz M, Piliponsky AM, Weller K, Chatterjea D, Clouthier DE, Yanagisawa MM, Tsai M, Galli SJ (November 2004). "Mast cells promote homeostasis by limiting endothelin-1-induced toxicity". Nature. 432 (7016): 512–6. Bibcode:2004Natur.432..512M. doi:10.1038/nature03085. PMID 15543132. S2CID 4426921.
14. Benoist C, Mathis D (19 December 2002). "Mast cells in autoimmune disease". Nature. 420 (6917): 875–8. Bibcode:2002Natur.420..875B. doi:10.1038/nature01324. PMID 12490961. S2CID 4391692.
15. Guo XJ, Wang YY, Zhang HY, Jin QQ, Gao CR (December 2015). "Mast cell tryptase and carboxypeptidase A expression in body fluid and gastrointestinal tract associated with drug-related fatal anaphylaxis". World Journal of Gastroenterology. 21 (47): 13288–93. doi:10.3748/wjg.v21.i47.13288. PMC 4679760. PMID 26715811.
16. Dougherty RH, Sidhu SS, Raman K, Solon M, Solberg OD, Caughey GH, Woodruff PG, Fahy JV (May 2010). "Accumulation of intraepithelial mast cells with a unique protease phenotype in T(H)2-high asthma". The Journal of Allergy and Clinical Immunology. 125 (5): 1046–1053.e8. doi:10.1016/j.jaci.2010.03.003. PMC 2918406. PMID 20451039.
17. Takabayashi T, Kato A, Peters AT, Suh LA, Carter R, Norton J, Grammer LC, Tan BK, Chandra RK, Conley DB, Kern RC, Fujieda S, Schleimer RP (August 2012). "Glandular mast cells with distinct phenotype are highly elevated in chronic rhinosinusitis with nasal polyps". The Journal of Allergy and Clinical Immunology. 130 (2): 410–20.e5. doi:10.1016/j.jaci.2012.02.046. PMC 3408832. PMID 22534535.
18. Schwartz LB, Riedel C, Schratz JJ, Austen KF (March 1982). "Localization of carboxypeptidase A to the macromolecular heparin proteoglycan-protein complex in secretory granules of rat serosal mast cells". Journal of Immunology. 128 (3): 1128–33. doi:10.4049/jimmunol.128.3.1128. PMID 6799569. S2CID 28893073.
19. Ryan CA (September 1971). "Inhibition of carboxypeptidase A by a naturally occurring polypeptide from potatoes". Biochemical and Biophysical Research Communications. 44 (5): 1265–70. doi:10.1016/s0006-291x(71)80222-x. PMID 5160409.
20. Miller LA, Cochrane DE, Feldberg RS, Carraway RE (June 1998). "Inhibition of neurotensin-stimulated mast cell secretion and carboxypeptidase A activity by the peptide inhibitor of carboxypeptidase A and neurotensin-receptor antagonist SR 48692". International Archives of Allergy and Immunology. 116 (2): 147–53. doi:10.1159/000023938. PMID 9652308. S2CID 46753844.
21. Normant E, Martres MP, Schwartz JC, Gros C (December 1995). "Purification, cDNA cloning, functional expression, and characterization of a 26-kDa endogenous mammalian carboxypeptidase inhibitor". Proceedings of the National Academy of Sciences of the United States of America. 92 (26): 12225–9. Bibcode:1995PNAS...9212225N. doi:10.1073/pnas.92.26.12225. PMC 40329. PMID 8618874.
22. Piliponsky AM, Chen CC, Nishimura T, Metz M, Rios EJ, Dobner PR, Wada E, Wada K, Zacharias S, Mohanasundaram UM, Faix JD, Abrink M, Pejler G, Pearl RG, Tsai M, Galli SJ (April 2008). "Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis". Nature Medicine. 14 (4): 392–8. doi:10.1038/nm1738. PMC 2873870. PMID 18376408.

External links

• Human CPA3 genome location and CPA3 gene details page in the UCSC Genome Browser.

Further reading

• Natsuaki M, Stewart CB, Vanderslice P, Schwartz LB, Natsuaki M, Wintroub BU, Rutter WJ, Goldstein SM (August 1992). "Human skin mast cell carboxypeptidase: functional characterization, cDNA cloning, and genealogy". The Journal of Investigative Dermatology. 99 (2): 138–45. doi:10.1111/1523-1747.ep12616776. PMID 1629626.
• Goldstein SM, Kaempfer CE, Proud D, Schwartz LB, Irani AM, Wintroub BU (October 1987). "Detection and partial characterization of a human mast cell carboxypeptidase". Journal of Immunology. 139 (8): 2724–9. doi:10.4049/jimmunol.139.8.2724. PMID 2443571. S2CID 12242134.
• Reynolds DS, Gurley DS, Stevens RL, Sugarbaker DJ, Austen KF, Serafin WE (December 1989). "Cloning of cDNAs that encode human mast cell carboxypeptidase A, and comparison of the protein with mouse mast cell carboxypeptidase A and rat pancreatic carboxypeptidases". Proceedings of the National Academy of Sciences of the United States of America. 86 (23): 9480–4. Bibcode:1989PNAS...86.9480R. doi:10.1073/pnas.86.23.9480. PMC 298520. PMID 2594780.
• Goldstein SM, Kaempfer CE, Kealey JT, Wintroub BU (May 1989). "Human mast cell carboxypeptidase. Purification and characterization". The Journal of Clinical Investigation. 83 (5): 1630–6. doi:10.1172/JCI114061. PMC 303870. PMID 2708524.
• Pascual R, Burgos FJ, Salva M, Soriano F, Mendez E, Aviles FX (February 1989). "Purification and properties of five different forms of human procarboxypeptidases". European Journal of Biochemistry. 179 (3): 609–16. doi:10.1111/j.1432-1033.1989.tb14590.x. PMID 2920728.
• Dikov MM, Springman EB, Yeola S, Serafin WE (October 1994). "Processing of procarboxypeptidase A and other zymogens in murine mast cells". The Journal of Biological Chemistry. 269 (41): 25897–904. doi:10.1016/S0021-9258(18)47330-9. PMID 7929294.
• Chen ZQ, He SH (February 2004). "Cloning and expression of human colon mast cell carboxypeptidase". World Journal of Gastroenterology. 10 (3): 342–7. doi:10.3748/wjg.v10.i3.342. PMC 4724900. PMID 14760754.