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. 2003 Apr 15;371(Pt 2):631–640. doi: 10.1042/BJ20021555

Complement C1r and C1s genes are duplicated in the mouse: differential expression generates alternative isomorphs in the liver and in the male reproductive system.

Gérard Garnier 1, Antonella Circolo 1, Yuanyuan Xu 1, John E Volanakis 1
PMCID: PMC1223281  PMID: 12513694

Abstract

C1r and C1s are the serine proteases that form the catalytic unit of the C1 complex, the first component of complement. In the present study, we found that the genes encoding murine C1r and C1s are duplicated. One set of these genes, referred to as c1rA and c1sA, are primarily expressed in the liver and are therefore the homologues of the human C1r and C1s genes. The other two genes, termed c1rB and c1sB, are expressed exclusively in male reproductive tissues, specifically the coagulating gland and the prostate. The predicted C1rB and C1sB proteins share 96 and 93% amino acid identity with C1rA and C1sA respectively. Most of the substitutions are clustered in the serine protease domains, suggesting differences in catalytic efficiencies and/or substrate specificities or alternatively adaptation to different physiological environments. The high homology of C1rB and C1sB with C1rA and C1sA in the non-catalytic regions indicates that they are probably capable of assembling the C1 complex. The expression of alternative genes encoding isomorphs of activating components of complement in male reproductive tissues raises the possibility of new mechanisms of complement activation in the male genital tract or of novel functions for complement proteases in reproduction.

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Selected References

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  1. Anderson D. J., Abbott A. F., Jack R. M. The role of complement component C3b and its receptors in sperm-oocyte interaction. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10051–10055. doi: 10.1073/pnas.90.21.10051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arlaud G. J., Gaboriaud C., Thielens N. M., Rossi V., Bersch B., Hernandez J. F., Fontecilla-Camps J. C. Structural biology of C1: dissection of a complex molecular machinery. Immunol Rev. 2001 Apr;180:136–145. doi: 10.1034/j.1600-065x.2001.1800112.x. [DOI] [PubMed] [Google Scholar]
  3. Arlaud G. J., Volanakis J. E., Thielens N. M., Narayana S. V., Rossi V., Xu Y. The atypical serine proteases of the complement system. Adv Immunol. 1998;69:249–307. [PubMed] [Google Scholar]
  4. Bersch B., Hernandez J. F., Marion D., Arlaud G. J. Solution structure of the epidermal growth factor (EGF)-like module of human complement protease C1r, an atypical member of the EGF family. Biochemistry. 1998 Feb 3;37(5):1204–1214. doi: 10.1021/bi971851v. [DOI] [PubMed] [Google Scholar]
  5. Bozas S. E., Kirszbaum L., Sparrow R. L., Walker I. D. Several vascular complement inhibitors are present on human sperm. Biol Reprod. 1993 Mar;48(3):503–511. doi: 10.1095/biolreprod48.3.503. [DOI] [PubMed] [Google Scholar]
  6. Budayova-Spano Monika, Lacroix Monique, Thielens Nicole M., Arlaud Gérard J., Fontecilla-Camps Juan Carlos, Gaboriaud Christine. The crystal structure of the zymogen catalytic domain of complement protease C1r reveals that a disruptive mechanical stress is required to trigger activation of the C1 complex. EMBO J. 2002 Feb 1;21(3):231–239. doi: 10.1093/emboj/21.3.231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Busby T. F., Ingham K. C. NH2-terminal calcium-binding domain of human complement C1s- mediates the interaction of C1r- with C1q. Biochemistry. 1990 May 15;29(19):4613–4618. doi: 10.1021/bi00471a016. [DOI] [PubMed] [Google Scholar]
  8. Busby W. H., Jr, Nam T. J., Moralez A., Smith C., Jennings M., Clemmons D. R. The complement component C1s is the protease that accounts for cleavage of insulin-like growth factor-binding protein-5 in fibroblast medium. J Biol Chem. 2000 Dec 1;275(48):37638–37644. doi: 10.1074/jbc.M006107200. [DOI] [PubMed] [Google Scholar]
  9. Byun S. J., Bahk Y. Y., Ryoo Z. Y., Kim K. E., Hwang H. Y., Lee J. W., Yi J. Y., Kim T. Y. Identification of cDNA encoding a serine protease homologous to human complement C1r precursor from grafted mouse skin. J Invest Dermatol. 2001 Mar;116(3):374–379. doi: 10.1046/j.1523-1747.2001.01257.x. [DOI] [PubMed] [Google Scholar]
  10. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  11. Cohen G. H., Silverton E. W., Davies D. R. Refined crystal structure of gamma-chymotrypsin at 1.9 A resolution. Comparison with other pancreatic serine proteases. J Mol Biol. 1981 Jun 5;148(4):449–479. doi: 10.1016/0022-2836(81)90186-8. [DOI] [PubMed] [Google Scholar]
  12. Colten H. R. Deficiencies of the first component of complement (C1): an update. Behring Inst Mitt. 1993 Dec;(93):287–291. [PubMed] [Google Scholar]
  13. Dahl M. R., Thiel S., Matsushita M., Fujita T., Willis A. C., Christensen T., Vorup-Jensen T., Jensenius J. C. MASP-3 and its association with distinct complexes of the mannan-binding lectin complement activation pathway. Immunity. 2001 Jul;15(1):127–135. doi: 10.1016/s1074-7613(01)00161-3. [DOI] [PubMed] [Google Scholar]
  14. Endo Y., Takahashi M., Nakao M., Saiga H., Sekine H., Matsushita M., Nonaka M., Fujita T. Two lineages of mannose-binding lectin-associated serine protease (MASP) in vertebrates. J Immunol. 1998 Nov 1;161(9):4924–4930. [PubMed] [Google Scholar]
  15. Eriksson H., Nissen M. H. Proteolysis of the heavy chain of major histocompatibility complex class I antigens by complement component C1s. Biochim Biophys Acta. 1990 Feb 9;1037(2):209–215. doi: 10.1016/0167-4838(90)90169-g. [DOI] [PubMed] [Google Scholar]
  16. Gaboriaud C., Rossi V., Bally I., Arlaud G. J., Fontecilla-Camps J. C. Crystal structure of the catalytic domain of human complement c1s: a serine protease with a handle. EMBO J. 2000 Apr 17;19(8):1755–1765. doi: 10.1093/emboj/19.8.1755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gasque P., Ischenko A., Legoedec J., Mauger C., Schouft M. T., Fontaine M. Expression of the complement classical pathway by human glioma in culture. A model for complement expression by nerve cells. J Biol Chem. 1993 Nov 25;268(33):25068–25074. [PubMed] [Google Scholar]
  18. Graf L., Craik C. S., Patthy A., Roczniak S., Fletterick R. J., Rutter W. J. Selective alteration of substrate specificity by replacement of aspartic acid-189 with lysine in the binding pocket of trypsin. Biochemistry. 1987 May 5;26(9):2616–2623. doi: 10.1021/bi00383a031. [DOI] [PubMed] [Google Scholar]
  19. Inoue N., Fukui A., Nomura M., Matsumoto M., Nishizawa Y., Toyoshima K., Seya T. A novel chicken membrane-associated complement regulatory protein: molecular cloning and functional characterization. J Immunol. 2001 Jan 1;166(1):424–431. doi: 10.4049/jimmunol.166.1.424. [DOI] [PubMed] [Google Scholar]
  20. Kinoshita H., Sakiyama H., Tokunaga K., Imajoh-Ohmi S., Hamada Y., Isono K., Sakiyama S. Complete primary structure of calcium-dependent serine proteinase capable of degrading extracellular matrix proteins. FEBS Lett. 1989 Jul 3;250(2):411–415. doi: 10.1016/0014-5793(89)80766-5. [DOI] [PubMed] [Google Scholar]
  21. Kusumoto H., Hirosawa S., Salier J. P., Hagen F. S., Kurachi K. Human genes for complement components C1r and C1s in a close tail-to-tail arrangement. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7307–7311. doi: 10.1073/pnas.85.19.7307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lawson P. R., Reid K. B. A novel PCR-based technique using expressed sequence tags and gene homology for murine genetic mapping: localization of the complement genes. Int Immunol. 2000 Mar;12(3):231–240. doi: 10.1093/intimm/12.3.231. [DOI] [PubMed] [Google Scholar]
  23. Legoedec J., Gasque P., Jeanne J. F., Scotte M., Fontaine M. Complement classical pathway expression by human skeletal myoblasts in vitro. Mol Immunol. 1997 Jul;34(10):735–741. doi: 10.1016/s0161-5890(97)00093-x. [DOI] [PubMed] [Google Scholar]
  24. Leytus S. P., Kurachi K., Sakariassen K. S., Davie E. W. Nucleotide sequence of the cDNA coding for human complement C1r. Biochemistry. 1986 Aug 26;25(17):4855–4863. doi: 10.1021/bi00365a020. [DOI] [PubMed] [Google Scholar]
  25. Miwa T., Nonaka M., Okada N., Wakana S., Shiroishi T., Okada H. Molecular cloning of rat and mouse membrane cofactor protein (MCP, CD46): preferential expression in testis and close linkage between the mouse Mcp and Cr2 genes on distal chromosome 1. Immunogenetics. 1998 Nov-Dec;48(6):363–371. doi: 10.1007/s002510050447. [DOI] [PubMed] [Google Scholar]
  26. Morris K. M., Aden D. P., Knowles B. B., Colten H. R. Complement biosynthesis by the human hepatoma-derived cell line HepG2. J Clin Invest. 1982 Oct;70(4):906–913. doi: 10.1172/JCI110687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nguyen V. C., Tosi M., Gross M. S., Cohen-Haguenauer O., Jegou-Foubert C., de Tand M. F., Meo T., Frézal J. Assignment of the complement serine protease genes C1r and C1s to chromosome 12 region 12p13. Hum Genet. 1988 Apr;78(4):363–368. doi: 10.1007/BF00291737. [DOI] [PubMed] [Google Scholar]
  28. Nonaka M. I., Wang G., Mori T., Okada H., Nonaka M. Novel androgen-dependent promoters direct expression of the C4b-binding protein alpha-chain gene in epididymis. J Immunol. 2001 Apr 1;166(7):4570–4577. doi: 10.4049/jimmunol.166.7.4570. [DOI] [PubMed] [Google Scholar]
  29. Perona J. J., Craik C. S. Evolutionary divergence of substrate specificity within the chymotrypsin-like serine protease fold. J Biol Chem. 1997 Nov 28;272(48):29987–29990. doi: 10.1074/jbc.272.48.29987. [DOI] [PubMed] [Google Scholar]
  30. Petry F., Reid K. B., Loos M. Gene expression of the A- and B-chain of mouse C1q in different tissues and the characterization of the recombinant A-chain. J Immunol. 1991 Dec 1;147(11):3988–3993. [PubMed] [Google Scholar]
  31. Qian Y. M., Qin X., Miwa T., Sun X., Halperin J. A., Song W. C. Identification and functional characterization of a new gene encoding the mouse terminal complement inhibitor CD59. J Immunol. 2000 Sep 1;165(5):2528–2534. doi: 10.4049/jimmunol.165.5.2528. [DOI] [PubMed] [Google Scholar]
  32. Ramadori G., Heinz H. P., Martin H., Meyer zum Büschenfelde K. H., Loos M. Biosynthesis of the subcomponents C1q, C1r and C1s of the first component of complement (C1) by guinea pig hepatocyte primary cultures. Eur J Immunol. 1986 Sep;16(9):1137–1141. doi: 10.1002/eji.1830160918. [DOI] [PubMed] [Google Scholar]
  33. Rooney I. A., Atkinson J. P., Krul E. S., Schonfeld G., Polakoski K., Saffitz J. E., Morgan B. P. Physiologic relevance of the membrane attack complex inhibitory protein CD59 in human seminal plasma: CD59 is present on extracellular organelles (prostasomes), binds cell membranes, and inhibits complement-mediated lysis. J Exp Med. 1993 May 1;177(5):1409–1420. doi: 10.1084/jem.177.5.1409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sackstein R., Colten H. R. Molecular regulation of MHC class III (C4 and factor B) gene expression in mouse peritoneal macrophages. J Immunol. 1984 Sep;133(3):1618–1626. [PubMed] [Google Scholar]
  35. Sakai H., Nakashima S., Yoshimura S., Nishimura Y., Sakai N., Nozawa Y. Molecular cloning of a cDNA encoding a serine protease homologous to complement C1s precursor from rat C6 glial cells and its expression during glial differentiation. Gene. 1998 Mar 16;209(1-2):87–94. doi: 10.1016/s0378-1119(98)00015-8. [DOI] [PubMed] [Google Scholar]
  36. Sakiyama H., Yamaguchi K., Chiba K., Nagata K., Taniyama C., Matsumoto M., Suzuki G., Tanaka T., Tomoasawa T., Yasukawa M. Biochemical characterization and tissue distribution of hamster complement C1s. J Immunol. 1991 Jan 1;146(1):183–187. [PubMed] [Google Scholar]
  37. Schaefer B. C. Revolutions in rapid amplification of cDNA ends: new strategies for polymerase chain reaction cloning of full-length cDNA ends. Anal Biochem. 1995 May 20;227(2):255–273. doi: 10.1006/abio.1995.1279. [DOI] [PubMed] [Google Scholar]
  38. Spicer A. P., Seldin M. F., Gendler S. J. Molecular cloning and chromosomal localization of the mouse decay-accelerating factor genes. Duplicated genes encode glycosylphosphatidylinositol-anchored and transmembrane forms. J Immunol. 1995 Sep 15;155(6):3079–3091. [PubMed] [Google Scholar]
  39. Steinbuch M., Audran R. The isolation of IgG from mammalian sera with the aid of caprylic acid. Arch Biochem Biophys. 1969 Nov;134(2):279–284. doi: 10.1016/0003-9861(69)90285-9. [DOI] [PubMed] [Google Scholar]
  40. Thielens N. M., Enrie K., Lacroix M., Jaquinod M., Hernandez J. F., Esser A. F., Arlaud G. J. The N-terminal CUB-epidermal growth factor module pair of human complement protease C1r binds Ca2+ with high affinity and mediates Ca2+-dependent interaction with C1s. J Biol Chem. 1999 Apr 2;274(14):9149–9159. doi: 10.1074/jbc.274.14.9149. [DOI] [PubMed] [Google Scholar]
  41. Tosi M., Duponchel C., Meo T., Couture-Tosi E. Complement genes C1r and C1s feature an intronless serine protease domain closely related to haptoglobin. J Mol Biol. 1989 Aug 20;208(4):709–714. doi: 10.1016/0022-2836(89)90161-7. [DOI] [PubMed] [Google Scholar]
  42. Tosi M., Duponchel C., Meo T., Julier C. Complete cDNA sequence of human complement Cls and close physical linkage of the homologous genes Cls and Clr. Biochemistry. 1987 Dec 29;26(26):8516–8524. doi: 10.1021/bi00400a004. [DOI] [PubMed] [Google Scholar]

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