Submitted June 5, 2007
Accepted December 5, 2007
Re-evaluation of the role of the protein S-C4b binding protein complex in activated protein C-catalyzed factor Va-inactivation
Lisbeth F.A. Maurissen, M. Christella L. G. D. Thomassen, Gerry A. F. Nicolaes, Bjorn Dahlback, Guido Tans, Jan Rosing, and Tilman M. Hackeng*
Department of Biochemistry, Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, Netherlands
Division of Clinical Chemistry, The Wallenberg Laboratory, University Hospital, Malmo, Lund University, Malmo, Sweden
* Corresponding author; email: t.hackeng{at}bioch.unimaas.nl.
Protein S expresses cofactor activity for activated protein C (APC) by enhancing the APC-catalyzed proteolysis at R306 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 R306 more than 10-fold, but instead inhibits proteolysis at R506 by APC 3- to 4-fold. Free protein S stimulates APC-catalyzed cleavage at R306 approximately 20-fold, and has no effect on cleavage at R506. 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 to 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 R506 of factor Va. These results are of interest for carriers of the factor VLeiden mutation (R506Q), as protein S-C4BP effectively enhances APC-catalyzed factor Va (R306) inactivation in plasma containing factor VLeiden.
