CPA3 explained

Carboxypeptidase A3 (mast cell carboxypeptidase A), also known as CPA3, is an enzyme which in humans is encoded by the CPA3 gene.^{[1] [2]} 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.^[3] 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.

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.^{[4] [3]}

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.^{[5] [6]} 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.^[7] CPA3 is also reported to have an important role in the protection towards snake venom toxins and vasoconstricting peptide endothelin 1(ET1).^{[8] [9]}

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.^[10] 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.^[11] 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.^{[12] [13]}

Interactions

CPA3 has been known to interact with:

• Heparin^[14]
• PCI^[15]
• SR48692^[16]
• Tissue carboxypeptidase inhibitor^[17]
• Neurotensin^[18]

Further reading

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

Notes and References

1. Web site: [0.0https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1359 Entrez Gene: CPA3 carboxypeptidase A3 (mast cell)].
2. Reynolds DS, Gurley DS, Austen KF . Cloning and characterization of the novel gene for mast cell carboxypeptidase A . The Journal of Clinical Investigation . 89 . 1 . 273–82 . January 1992 . 1729276 . 442845 . 10.1172/JCI115571 .
3. Huang H, Reed CP, Zhang JS, Shridhar V, Wang L, Smith DI . 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 . June 1999 . 10383164 .
4. . Signal sequences. The limits of variation . Journal of Molecular Biology . 184 . 1 . 99–105 . July 1985 . 4032478 . 10.1016/0022-2836(85)90046-4.
5. Kokkonen JO, Vartiainen M, Kovanen PT . 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 . December 1986 . 10.1016/S0021-9258(18)66677-3 . 3536921 . free .
6. Lundequist A, Tchougounova E, Abrink M, Pejler G . 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 . July 2004 . 15173164 . 10.1074/jbc.M405576200 . free .
7. Sanglas L, Aviles FX, Huber R, Gomis-Rüth FX, Arolas JL . 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 . February 2009 . 19179285 . 10.1073/pnas.0812623106 . 2644108. 2009PNAS..106.1743S . free .
8. Metz M, Piliponsky AM, Chen CC, Lammel V, Abrink M, Pejler G, Tsai M, Galli SJ . Mast cells can enhance resistance to snake and honeybee venoms . Science . 313 . 5786 . 526–30 . July 2006 . 16873664 . 10.1126/science.1128877 . 2006Sci...313..526M . 30725308 .
9. Maurer M, Wedemeyer J, Metz M, Piliponsky AM, Weller K, Chatterjea D, Clouthier DE, Yanagisawa MM, Tsai M, Galli SJ . Mast cells promote homeostasis by limiting endothelin-1-induced toxicity . Nature . 432 . 7016 . 512–6 . November 2004 . 15543132 . 10.1038/nature03085 . 2004Natur.432..512M . 4426921 .
10. Benoist C, Mathis D . Mast cells in autoimmune disease . Nature . 420 . 6917 . 875–8 . 19 December 2002 . 12490961 . 10.1038/nature01324 . 2002Natur.420..875B . 4391692 .
11. Guo XJ, Wang YY, Zhang HY, Jin QQ, Gao CR . 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 . December 2015 . 26715811 . 10.3748/wjg.v21.i47.13288 . 4679760 . free .
12. Dougherty RH, Sidhu SS, Raman K, Solon M, Solberg OD, Caughey GH, Woodruff PG, Fahy JV . 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 . May 2010 . 20451039 . 10.1016/j.jaci.2010.03.003 . 2918406.
13. 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 . 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 . August 2012 . 22534535 . 10.1016/j.jaci.2012.02.046 . 3408832.
14. Schwartz LB, Riedel C, Schratz JJ, Austen KF . 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 . March 1982 . 10.4049/jimmunol.128.3.1128 . 6799569 . 28893073 . free .
15. Ryan CA . Inhibition of carboxypeptidase A by a naturally occurring polypeptide from potatoes . Biochemical and Biophysical Research Communications . 44 . 5 . 1265–70 . September 1971 . 5160409 . 10.1016/s0006-291x(71)80222-x.
16. Miller LA, Cochrane DE, Feldberg RS, Carraway RE . 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 . June 1998 . 9652308 . 10.1159/000023938. 46753844 .
17. Normant E, Martres MP, Schwartz JC, Gros C . 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 . December 1995 . 8618874 . 10.1073/pnas.92.26.12225 . 40329. 1995PNAS...9212225N . free .
18. 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 . Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis . Nature Medicine . 14 . 4 . 392–8 . April 2008 . 18376408 . 10.1038/nm1738 . 2873870.