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Blood, 15 March 2008, Vol. 111, No. 6, pp. 3034-3041. Prepublished online as a Blood First Edition Paper on December 26, 2007; DOI 10.1182/blood-2007-06-089987. This Article Full Text (PDF) All Versions of this Article: blood-2007-06-089987v1 111/6/3034    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Maurissen, L. F.A. Articles by Hackeng, T. M. Search for Related Content PubMed PubMed Citation Articles by Maurissen, L. F.A. Articles by Hackeng, T. M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. M. Hackeng and J. Rosing Protein S as Cofactor for TFPI Arterioscler Thromb Vasc Biol, December 1, 2009; 29(12): 2015 - 2020. [Abstract] [Full Text] [PDF] J. C McCann and B. N Ames Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging? Am. J. Clinical Nutrition, October 1, 2009; 90(4): 889 - 907. [Abstract] [Full Text] [PDF] F. Saller, A. C. Brisset, S. N. Tchaikovski, M. Azevedo, R. Chrast, J. A. Fernandez, M. Schapira, T. M. Hackeng, J. H. Griffin, and A. Angelillo-Scherrer Generation and phenotypic analysis of protein S-deficient mice Blood, September 10, 2009; 114(11): 2307 - 2314. [Abstract] [Full Text] [PDF] W. M. Lijfering, R. Mulder, M. K. ten Kate, N. J. G. M. Veeger, A. B. Mulder, and J. van der Meer Clinical relevance of decreased free protein S levels: results from a retrospective family cohort study involving 1143 relatives Blood, February 5, 2009; 113(6): 1225 - 1230. [Abstract] [Full Text] [PDF]

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