Re-evaluation of the role of the protein S-C4b binding protein complex in activated protein C-catalyzed factor Va-inactivation

Summary, in English

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 R306, but by generation of a specific inhibitor for APC-catalyzed 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.

• Författare: Lisbeth F A Maurissen; M. Christella L G D Thomassen; Gerry A F Nicolaes; Björn Dahlbäck; Guido Tans; Jan Rosing; Tilman M Hackeng
• Avdelning/ar: Klinisk kemi, Malmö
• Publiceringsår: 2008
• Språk: Engelska
• Sidor: 3034-3041
• Publikation/Tidskrift/Serie: Blood
• Volym: 111
• Issue: 6
• Länkar: http://dx.doi.org/10.1182/blood-2007-06-089987
• Dokumenttyp: Artikel i tidskrift
• Förlag: American Society of Hematology
• Ämne: Hematology
• Status: Published
• Forskningsgrupp: Clinical Chemistry, Malmö
• ISBN/ISSN/Övrigt: ISSN: 1528-0020