title: Re-evaluation of the role of the protein S-C4b binding protein complex in activated protein C-catalyzed factor Va-inactivation.
abstract: Protein S expresses cofactor activity for activated protein C (APC) by enhancing the APC-catalyzed proteolysis at R(306) in factor Va. It is generally accepted that only free protein S is active and that complex formation with C4b-binding protein (C4BP) inhibits the APC-cofactor activity of protein S. However, the present study shows that protein S-C4BP expresses APC-cofactor activity and stimulates APC-catalyzed proteolysis at R(306) more than 10-fold, but instead inhibits proteolysis at R(506) by APC 3- to 4-fold. Free protein S stimulates APC-catalyzed cleavage at R(306) approximately 20-fold and has no effect on cleavage at R(506). The resulting net effect of protein S-C4BP complex formation on APC-catalyzed factor Va inactivation is a 6- to 8-fold reduction in factor Va inactivation when compared with free protein S, which is not explained by inhibition of APC-cofactor activity of protein S at R(306), but by generation of a specific inhibitor for APCcatalyzed proteolysis at R(506) of factor Va. These results are of interest for carriers of the factor V(Leiden) mutation (R(506)Q), as protein S-C4BP effectively enhances APC-catalyzed factor Va (R(306)) inactivation in plasma containing factor V(Leiden).
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, the Netherlands.
authors.forename: Lisbeth F A
authors.initials: LF
authors.lastname: Maurissen
authors.forename: M Christella L G D
authors.initials: MC
authors.lastname: Thomassen
authors.forename: Gerry A F
authors.initials: GA
authors.lastname: Nicolaes
authors.forename: Björn
authors.initials: B
authors.lastname: Dahlbäck
authors.forename: Guido
authors.initials: G
authors.lastname: Tans
authors.forename: Jan
authors.initials: J
authors.lastname: Rosing
authors.forename: Tilman M
authors.initials: TM
authors.lastname: Hackeng
mesh_terms: D000938:Antigen-Presenting Cells / Q000378:metabolism; D002384:Catalysis; D002850:Chromatography, Gel; D050716:Complement C4b-Binding Protein / Q000378:metabolism*; D005169:Factor VIII / Q000378:metabolism; D015943:Factor Va / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D011486:Protein C / Q000378:metabolism*; D017293:Protein S / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism
chemical_list: D050716:Complement C4b-Binding Protein; D011486:Protein C; D017293:Protein S; D015943:Factor Va; D005169:Factor VIII; D013917:Thrombin