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

Maurissen, Lisbeth F A; Thomassen, M. Christella L G D; Nicolaes, Gerry A F; Dahlbäck, Björn LU ; Tans, Guido; Rosing, Jan and Hackeng, Tilman M (2008) In Blood 111(6). p.3034-3041
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-... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
111
issue
6
pages
3034 - 3041
publisher
American Society of Hematology
external identifiers
  • wos:000254009600016
  • scopus:42449084553
ISSN
1528-0020
DOI
10.1182/blood-2007-06-089987
language
English
LU publication?
yes
id
b40752fa-8e9b-4900-b195-a9a991c52c2b (old id 1185149)
date added to LUP
2008-09-02 16:02:43
date last changed
2017-08-27 04:06:34
@article{b40752fa-8e9b-4900-b195-a9a991c52c2b,
  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 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.},
  author       = {Maurissen, Lisbeth F A and Thomassen, M. Christella L G D and Nicolaes, Gerry A F and Dahlbäck, Björn and Tans, Guido and Rosing, Jan and Hackeng, Tilman M},
  issn         = {1528-0020},
  language     = {eng},
  number       = {6},
  pages        = {3034--3041},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Re-evaluation of the role of the protein S-C4b binding protein complex in activated protein C-catalyzed factor Va-inactivation},
  url          = {http://dx.doi.org/10.1182/blood-2007-06-089987},
  volume       = {111},
  year         = {2008},
}