Abstract
Protein C is a vitamin K-dependent plasma glycoprotein that, after activation by thrombin-thrombomodulin upon the endothelial cell surface, serves as a feedback down-regulator of the coagulation cascade by specifically degrading the protein cofactors VIIIa and Va (Figure 1). The biological role of protein C and the vascular endothelium has been recently reviewed in a succinct fashion1. Protein C in a less understood manner also enhances the process of fibrinolysis. Because of its antithrombotic as well as pro-fibrinolytic properties, protein C is considered to be a potential agent for antithrombotic therapy and a candidate for production by recombinant DNA technologies. The scope of this paper is to review: (i) the organization of the human protein C gene, particularly as it relates to the genes for homologous vitamin K-dependent proteins and to genetic protein C deficiency; and (ii) the biosynthesis of recombinant protein C in forms that are properly processed and biologically active.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Esmon NL, Esmon CT: Protein C and the endothelium. Sem in Thromb and Hemostas 14: 210, 1988
Foster D, Yoshitake S, Davie EW: The nucleotide sequence of the gene for human protein C. Proc Natl Acad Sci USA 82: 4673, 1985
Plutzky J, Hoskins JA, Long GL, Crabtree GR: Evolution and organization of the human protein C gene. Proc Natl Acad Sci USA 83: 546, 1986
Beckmann RJ, Schmidt RJ, Santerre RF, Plutzky J, Crabtree GR, Long GL: The structure and evolution of a 461 amino acid human protein C precursor and its messenger RNA, based upon the DNA sequence of cloned human liver cDNAs. Nuc Acids Res 13: 5233, 1985
Deininger PL, Jolly DJ, Rubin CM, Friedman T, Schmid CW: Base sequence studies of 300 nucleotide renatured repeated human DNA clones. J Mol Biol 151: 17, 1981
Rocchi M, Roncuzzi L, Santamaria R, Archidiacono N, Dente N, Romeo G: Mapping through somatic cell hybrids and cDNA probes of protein C to chromosome 2, factor X to chromosome 13, and α1-acid glycoprotein to chromosome 9. Hum Genet 74: 30, 1986
Long GL, Marshall A, Gardner JC, Naylor SL: Genes for human vitamin K-dependent plasma proteins C and S are located on chromosomes 2 and 3, respectively. Somat Cell and Molec Genet 14: 93, 1988
Furie B, Furie BC: The molecular basis of blood coagulation. Cell 53: 505, 1988
Patthy L: Evolution of the proteases of blood coagulation and fibrinolysis by assembly from modules. Cell 41: 657, 1985
Gilbert W: Why genes in pieces? Nature 271: 501, 1978
Soriano-Garcia M, Park CH, Tulinsky A, Ravichandran KG, Skrzypczak-Jankun E: Structure of Ca2+ prothrombin fragment 1 including the conformation of the Gla domain. Biochemistry 28: 6805, 1989
Banyai L, Varadi A, Patthy L: Common evolutionary origin of the fibrin-binding structures of fibronectin and tissue-type plasminogen activator. FEBS Lett 163: 37, 1983.
Long GL: Structure and evolution of the human genes encoding protein C and coagulation factors VII, IX, and X. Cold Spr Harbor Symp 51: 525, 1986
Broekmans AW, van der Linden IK, Velkamp JJ, Bertina RM: Prevalence of isolated protein C deficiency in patients with venous thrombotic disease and in the population. Thromb Haemost 50: 350, 1983
Miletich J, Sherman L, Brose G: Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 317: 991, 1987
Crabtree GR, Plutzky J, Marier R, Griffin J, Zarcharski L, Gruppo R, Sela N, Long G: Analysis of the organization of the human protein C gene in normal and protein C deficient individuals. Blood 64: 261, 1984
Matsuda M, Sugo T, Sakata Y, Murayama H, Mimuro J, Tanabe S, Yoshitake S: A thrombotic state due to an abnormal protein C. N Engl J Med 319: 1265, 1988
Grundy C, Chitolie A, Talbot S, Bevan D, Kakkar V, Cooper DN: Protein C London 1: recurrent mutation at Arg 169 (CGG→TGG) in the protein C gene causing thrombosis. Nuc Acids Res 17: 10513, 1989
Romeo G, Hassan HJ, Staempfli S, Roncuzzi L, Cianetti L, Leonardi A, Vincent V, Mannucci PM, Bertina R, Peschle C, Cortease R: Hereditary thrombophilia: Identification of nonsense and missense mutations in the protein C gene. Proc Natl Acad Sci USA 84: 2829, 1987
Long GL, Belagaje RM, MacGillivray RTA: Cloning and sequencing of liver cDNA coding for bovine protein C. Proc Natl Acad Sci USA 81: 5653, 1984
Pan LC, Price PA: The propeptide of rat bone γ-carboxyglutamic acid protein shares homology with other vitamin K-dependent protein precursors. Proc Natl Acad Sci USA 82: 6109, 1985
Suttie JW, Hoskins JA, Engleke J, Hopfgartner A, Ehrlich H, Bang NU, Belagaje RM, Schoner B, Long GL: Vitamin K-dependent carboxylase: Possible role of the substrate “propeptide” as an intracellular recognition site. Proc Natl Acad Sci USA 84: 634, 1987
Foster DC, Rudinski MS, Schach BG, Berkner KL, Kumar AA, Hagen FS, Sprecher CA, Insley MY, Davie EW: Propeptide of human protein C is necessary for γ-carboxylation. Biochemistry 26: 7003, 1987
Walls JD, Berg DT, Yan SB, Grinnell BW: Amplification of multicistronic plasmids in the human 293 cell line and secretion of correctly processed recombinant human protein C. Gene 81: 139, 1989
Ehrlich HJ, Jaskunas SR, Ginnell BW, Yan SB, Bang NU: Direct expression of recombiant activated human protein C, a serine protease. J Biol Chem 264: 14298, 1989
Foster DC, Sprecher CA, Holly RD, Gambee JE, Walker KM, Kumar AA: Endoproteolytic processing of the dibasic cleavage site in the human protein C precursor in transfected mammalian cells: Effects of sequence alterations on efficiency of cleavage. Biochemistry 29: 347, 1990
Yoshitake S, Schach BG, Foster DC, Davie EW, Kurachi K: Nucleotide sequence of the gene for human factor IX (Anti-hemophilie factor B). Biochemistry 24: 3736, 1985.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1991 Springer Science+Business Media New York
About this chapter
Cite this chapter
Long, G.L. (1991). Protein C: Gene Structure and Protein Synthesis. In: Hoyer, L.W., Drohan, W.N. (eds) Recombinant Technology in Hemostasis and Thrombosis. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-3698-7_5
Download citation
DOI: https://doi.org/10.1007/978-1-4615-3698-7_5
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-6644-7
Online ISBN: 978-1-4615-3698-7
eBook Packages: Springer Book Archive