Abstract
Serine proteases constitute the major protein granule content of cells of several hematopoietic cell lineages. A subgroup of these proteases, including the mast cell chymases, neutrophil cathepsin G, and T cell granzymes B to F and N, are in all investigated mammals encoded in one locus, the chymase locus. It is interesting to note that this locus has diversified greatly during the last 95 Myr of mammalian evolution. This divergence is exemplified by the presence of Mcpt8-related genes and multiple β-chymases in the mouse and rat, which lack direct counterparts in primates and in seven functional granzyme genes in the mouse where the human locus has only two. To study the expansion of the locus during rodent evolution and to better understand the evolutionary origin of β-chymases and the Mcpt8-family, we have performed a detailed analysis of the chymase locus of four mammalian species, i.e., human, dog, mouse, and rat. As a result, we report here a second chymase-like gene in dog, Cma2, which clusters with β-chymases in phylogenetic analyses. This finding supports a duplication of the common ancestor for α- and β-chymases before the major radiation of placental mammals, and a loss of the ancestral β-chymase gene sometime during primate evolution. Moreover, we show that in the rat, the Mcpt8-family diversified relatively recently together with sequences related to the β-chymase Mcpt2. Eight novel genes were identified in the duplication region, four of which are predicted to be functional. Duplications of rat granzyme B- and C-like sequences occurred seemingly independently within a similar time frame, but did not give rise to functional genes. Due to the duplications in rat and deletions in the carnivore/primate lineage, the rat chymase locus is approximately 15 and 9 times larger than its counterparts in dog and human, respectively. These findings illustrate the importance of gene duplications in conferring rapid changes in mammalian genomes.
Similar content being viewed by others
Abbreviations
- aa:
-
amino acid
- indels:
-
insertions and/or deletions
- Myr:
-
million years
- MC:
-
mast cell
- MMC:
-
mucosal mast cells
- CTMC:
-
connective tissue mast cells
- mMCP:
-
mouse mast cell protease (protein)
- rMCP:
-
rat mast cell protease (protein)
- Mcpt:
-
mast cell protease (protein)
- Mcpt :
-
mast cell protease (gene)
- M/R8-family:
-
mouse/rat Mcpt8-family
- R8-family:
-
rat Mcpt8-family
- M1/R2-family:
-
mouse Mcpt1-/rat Mcpt2-family
- R2-family:
-
rat Mcpt2-family
References
Baumgartner RA, Deramo VA, Beaven MA (1996) Constitutive and inducible mechanisms for synthesis and release of cytokines in immune cell lines. J Immunol 157:4087–4093
Benfey PN, Yin FH, Leder P (1987) Cloning of the mast cell protease, RMCP II. Evidence for cell-specific expression and a multi-gene family. J Biol Chem 262:5377–5384
Breathnach R, Chambon P (1981) Organization and expression of eucaryotic split genes coding for proteins. Annu Rev Biochem 50:349–383
Burset M, Seledtsov IA, Solovyev VV (2000) Analysis of canonical and non-canonical splice sites in mammalian genomes. Nucleic Acids Res 28:4364–4375
Campanelli D, Detmers PA, Nathan CF, Gabay JE (1990) Azurocidin and a homologous serine protease from neutrophils. Differential antimicrobial and proteolytic properties. J Clin Invest 85:904–915
Caughey GH (2005) Origins of functional diversity in mammalian mast cell peptidases. The Batsheva de Rothschild international workshop on mast cell signalling and function in health and disease. Eilat, Israel
Caughey GH, Schaumberg TH, Zerweck EH, Butterfield JH, Hanson RD, Silverman GA, Ley TJ (1993) The human mast cell chymase gene (CMA1): mapping to the cathepsin G/granzyme gene cluster and lineage-restricted expression. Genomics 15:614–620
Caughey GH, Raymond WW, Wolters PJ (2000) Angiotensin II generation by mast cell alpha- and beta-chymases. Biochim Biophys Acta 1480:245–257
Chandrasekharan UM, Sanker S, Glynias MJ, Karnik SS, Husain A (1996) Angiotensin II-forming activity in a reconstructed ancestral chymase. Science 271:502–505
Felsenstein J (1989) PHYLIP—phylogeny interference package (version 3.2). Cladistics 5:164–166
Gibbs RA, Weinstock GM, Metzker ML, Muzny DM, Sodergren EJ, Scherer S, Scott G, Steffen D, Worley KC, Burch PE, Okwuonu G, Hines S, Lewis L, DeRamo C, Delgado O, Dugan-Rocha S, Miner G, Morgan M,Hawes A, Gill R, Celera, Holt RA, Adams MD, Amanatides PG, Baden-Tillson H, Barnstead M, Chin S, Evans CA, Ferriera S, Fosler C, Glodek A, Gu Z, Jennings D, Kraft CL, Nguyen T, Pfannkoch CM, Sitter C, Sutton GG, Venter JC, Woodage T, Smith D, Lee HM, Gustafson E, Cahill P, Kana A, Doucette-Stamm L, Weinstock K, Fechtel K, Weiss RB, Dunn DM, Green ED, Blakesley RW, Bouffard GG, De Jong PJ, Osoegawa K, Zhu B, Marra M, Schein J, Bosdet I, Fjell C, Jones S, Krzywinski M, Mathewson C, Siddiqui A, Wye N, McPherson J, Zhao S, Fraser CM, Shetty J, Shatsman S, Geer K, Chen Y, Abramzon S, Nierman WC, Havlak PH, Chen R, Durbin KJ, Egan A, Ren Y, Song XZ, Li B, Liu Y, Qin X, Cawley S, Cooney AJ, D’Souza LM, Martin K, Wu JQ, Gonzalez-Garay ML, Jackson AR, Kalafus KJ, McLeod MP, Milosavljevic A, Virk D, Volkov A, Wheeler DA, Zhang Z, Bailey JA, Eichler EE, Tuzun E et al (2004) Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature 428:493–521
Grossman WJ, Revell PA, Lu ZH, Johnson H, Bredemeyer AJ, Ley TJ (2003) The orphan granzymes of humans and mice. Curr Opin Immunol 15:544–552
Grus WE, Shi P, Zhang YP, Zhang J (2005) Dramatic variation of the vomeronasal pheromone receptor gene repertoire among five orders of placental and marsupial mammals. Proc Natl Acad Sci USA 102:5767–5772
Guo C, Ju H, Leung D, Massaeli H, Shi M, Rabinovitch M (2001) A novel vascular smooth muscle chymase is upregulated in hypertensive rats. J Clin Invest 107:703–715
Gurish MF, Nadeau JH, Johnson KR, McNeil HP, Grattan KM, Austen KF, Stevens RL (1993) A closely linked complex of mouse mast cell-specific chymase genes on chromosome 14. J Biol Chem 268:11372–11379
Hao L, Nei M (2004) Genomic organization and evolutionary analysis of Ly49 genes encoding the rodent natural killer cell receptors: rapid evolution by repeated gene duplication. Immunogenetics 56:343–354
Hoit BD, Shao Y, Kinoshita A, Gabel M, Husain A, Walsh RA (1995) Effects of angiotensin II generated by an angiotensin converting enzyme-independent pathway on left ventricular performance in the conscious baboon. J Clin Invest 95:1519–1527
Huang R, Hellman L (1994) Genes for mast-cell serine protease and their molecular evolution. Immunogenetics 40:397–414
Huang RY, Blom T, Hellman L (1991) Cloning and structural analysis of MMCP-1, MMCP-4 and MMCP-5, three mouse mast cell-specific serine proteases. Eur J Immunol 21:1611–1621
Huang C, Li L, Krilis SA, Chanasyk K, Tang Y, Li Z, Hunt JE, Stevens RL (1999) Human tryptases alpha and beta/II are functionally distinct due, in part, to a single amino acid difference in one of the surface loops that forms the substrate-binding cleft. J Biol Chem 274:19670–19676
Humphries DE, Wong GW, Friend DS, Gurish MF, Qiu WT, Huang C, Sharpe AH, Stevens RL (1999) Heparin is essential for the storage of specific granule proteases in mast cells. Nature 400:769–772
Hunt JE, Friend DS, Gurish MF, Feyfant E, Sali A, Huang C, Ghildyal N, Stechschulte S, Austen KF, Stevens RL (1997) Mouse mast cell protease 9, a novel member of the chromosome 14 family of serine proteases that is selectively expressed in uterine mast cells. J Biol Chem 272:29158–29166
Ide H, Itoh H, Tomita M, Murakumo Y, Kobayashi T, Maruyama H, Osada Y, Nawa Y (1995) Cloning of the cDNA encoding a novel rat mast-cell proteinase, rMCP-3, and its expression in comparison with other rat mast-cell proteinases. Biochem J 311(Pt 2):675–680
Jurka J, Klonowski P, Dagman V, Pelton P (1996) CENSOR—a program for identification and elimination of repetitive elements from DNA sequences. Comput Chem 20:119–121
Karlson U (2003) Cutting edge-cleavage specificity and biochemical characterization of mast cell serine proteases. PhD thesis, Department of Cell and Molecular Biology, Uppsala University. ISBN 91-554-5699-5
Karlson U, Pejler G, Tomasini-Johansson B, Hellman L (2003) Extended substrate specificity of rat mast cell protease 5, a rodent alpha-chymase with elastase-like primary specificity. J Biol Chem 278:39625–39631
Kido H, Izumi K, Otsuka H, Fukusen N, Kato Y, Katunuma NA (1986) Chymotrypsin-type serine protease in rat basophilic leukemia cells: evidence for its immunologic identity with atypical mast cell protease. J Immunol 136:1061–1065
Le Trong H, Parmelee DC, Walsh KA, Neurath H, Woodbury RG (1987) Amino acid sequence of rat mast cell protease I (chymase). Biochemistry 26:6988–6994
Lützelschwab C, Pejler G, Aveskogh M, Hellman L (1997) Secretory granule proteases in rat mast cells. Cloning of 10 different serine proteases and a carboxypeptidase A from various rat mast cell populations. J Exp Med 185:13–29
Lützelschwab C, Huang MR, Kullberg MC, Aveskogh M, Hellman L (1998) Characterization of mouse mast cell protease-8, the first member of a novel subfamily of mouse mast cell serine proteases, distinct from both the classical chymases and tryptases. Eur J Immunol 28:1022–1033
Marquardt U, Zettl F, Huber R, Bode W, Sommerhoff C (2002) The crystal structure of human alpha1-tryptase reveals a blocked substrate-binding region. J Mol Biol 321:491–502
Morgan JG, Sukiennicki T, Pereira HA, Spitznagel JK, Guerra ME, Larrick JW (1991) Cloning of the cDNA for the serine protease homolog CAP37/azurocidin, a microbicidal and chemotactic protein from human granulocytes. J Immunol 147:3210–3214
Neurath H (1986) The versatility of proteolytic enzymes. J Cell Biochem 32:35–49
Newlands GF, Gibson S, Knox DP, Grencis R, Wakelin D, Miller HR (1987) Characterization and mast cell origin of a chymotrypsin-like proteinase isolated from intestines of mice infected with Trichinella spiralis. Immunology 62:629–634
Nylenna O, Naper C, Vaage JT, Woon PY, Gauguier D, Dissen E, Ryan JC, Fossum S (2005) The genes and gene organization of the Ly49 region of the rat natural killer cell gene complex. Eur J Immunol 35:261–272
Pejler G, Maccarana M (1994) Interaction of heparin with rat mast cell protease 1. J Biol Chem 269:14451–14456
Perona JJ, Craik CS (1995) Structural basis of substrate specificity in the serine proteases. Protein Sci 4:337–360
Poorafshar M, Helmby H, Troye-Blomberg M, Hellman L (2000) MMCP-8, the first lineage-specific differentiation marker for mouse basophils. Elevated numbers of potent IL-4-producing and MMCP-8-positive cells in spleens of malaria-infected mice. Eur J Immunol 30:2660–2668
Puente X (2005) A genomic view of the complexity of mammalian proteolytic systems. Biochemical Society Focused Meetings
Puente XS, Lopez-Otin C (2004) A genomic analysis of rat proteases and protease inhibitors. Genome Res 14:609–622
Savolainen P, Zhang YP, Luo J, Lundeberg J, Leitner T (2002) Genetic evidence for an East Asian origin of domestic dogs. Science 298:1610–1613
Serafin WE, Reynolds DS, Rogelj S, Lane WS, Conder GA, Johnson SS, Austen KF, Stevens RL (1990) Identification and molecular cloning of a novel mouse mucosal mast cell serine protease. J Biol Chem 265:423–429
Shi P, Zhang J, Yang H, Zhang YP (2003) Adaptive diversification of bitter taste receptor genes in Mammalian evolution. Mol Biol Evol 20:805–814
Solivan S, Selwood T, Wang ZM, Schechter NM (2002) Evidence for diversity of substrate specificity among members of the chymase family of serine proteases. FEBS Lett 512:133–138
Springer MS, Murphy WJ, Eizirik E, O’Brien SJ (2003) Placental mammal diversification and the Cretaceous-Tertiary boundary. Proc Natl Acad Sci USA 100:1056–1061
Takai S, Shiota Nm, Kobayashi S, Matsumura E, Miyazaki M (1997) Induction of chymase that forms angiotensin II in the monkey atherosclerotic aorta. FEBS Lett 412:86–90
Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG (1997) The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res 25:4876–4882
Trong HL, Newlands GF, Miller HR, Charbonneau H, Neurath H, Woodbury RG (1989) Amino acid sequence of a mouse mucosal mast cell protease. Biochemistry 28:391–395
Vernersson M, Aveskogh M, Hellman L (2004) Cloning of IgE from the echidna (Tachyglossus aculeatus) and a comparative analysis of epsilon chains from all three extant mammalian lineages. Dev Comp Immunol 28:61–75
Vila C, Savolainen P, Maldonado JE, Amorim IR, Rice JE, Honeycutt RL, Crandall KA, Lundeberg J, Wayne RK (1997) Multiple and ancient origins of the domestic dog. Science 276:1687–1689
Wintroub BU, Schechter NB, Lazarus GS, Kaempfer CE, Schwartz LB (1984) Angiotensin I conversion by human and rat chymotryptic proteinases. J Invest Dermatol 83:336–339
Wong GW, Yasuda S, Morokawa N, Li L, Stevens RL (2004) Mouse chromosome 17A3.3 contains 13 genes that encode functional tryptic-like serine proteases with distinct tissue and cell expression patterns. J Biol Chem 279:2438–2452
Yang Z (1997) PAML: a program package for phylogenetic analysis by maximum likelihood. Comput Appl Biosci 13:555–556
Yang Z, Nielsen R, Goldman N, Pedersen AM (2000) Codon-substitution models for heterogeneous selection pressure at amino acid sites. Genetics 155:431–449
Acknowledgements
We thank Dr. Robert Fredriksson for excellent advice on bioinformatic tools. We thank professor Lars Pilström and Jenny Reimer for critical reading of the manuscript. This work was funded by the Swedish Research Council.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gallwitz, M., Hellman, L. Rapid lineage-specific diversification of the mast cell chymase locus during mammalian evolution. Immunogenetics 58, 641–654 (2006). https://doi.org/10.1007/s00251-006-0123-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00251-006-0123-4