Document Detail


Re-evaluation of the role of the protein S-C4b binding protein complex in activated protein C-catalyzed factor Va-inactivation.
MedLine Citation:
PMID:  18160668     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Lisbeth F A Maurissen; M Christella L G D Thomassen; Gerry A F Nicolaes; Björn Dahlbäck; Guido Tans; Jan Rosing; Tilman M Hackeng
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-12-26
Journal Detail:
Title:  Blood     Volume:  111     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-03-11     Completed Date:  2008-04-25     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3034-41     Citation Subset:  AIM; IM    
Affiliation:
Department of Biochemistry, Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, the Netherlands.
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MeSH Terms
Descriptor/Qualifier:
Antigen-Presenting Cells / metabolism
Catalysis
Chromatography, Gel
Complement C4b-Binding Protein / metabolism*
Factor VIII / metabolism
Factor Va / genetics,  metabolism*
Humans
Mutation / genetics
Protein Binding
Protein C / metabolism*
Protein S / metabolism*
Thrombin / metabolism
Chemical
Reg. No./Substance:
0/Complement C4b-Binding Protein; 0/Protein C; 0/Protein S; 65522-14-7/Factor Va; 9001-27-8/Factor VIII; EC 3.4.21.5/Thrombin

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