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Blood, 1 January 2005, Vol. 105, No. 1, pp. 122-130. Prepublished online as a Blood First Edition Paper on August 12, 2004; DOI 10.1182/blood-2004-06-2176. This Article Full Text (PDF) All Versions of this Article: 2004-06-2176v1 105/1/122    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 Saller, F. Articles by Borgel, D. Search for Related Content PubMed PubMed Citation Articles by Saller, F. Articles by Borgel, D. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 9, 2004 Accepted July 22, 2004 The gamma-carboxyglutamic acid (Gla) domain of anticoagulant protein S is involved in activated protein C-cofactor activity, independently of phospholipid binding Francois Saller, Bruno O Villoutreix, Aymeric Amelot, Tahar Kaabache, Bernard F Le Bonniec, Martine Aiach, Sophie Gandrille, and Delphine Borgel* Faculte des Sciences Pharmaceutiques et Biologiques, IFR 71 'Sciences du Medicament', INSERM U428, Universite Paris V, Paris, France * Corresponding author; email: borgel{at}pharmacie.univ-paris5.fr. We expressed two chimeras between human protein S (PS) and human prothrombin (FII), in which the prothrombin Gla domain replaced the PS Gla domain in native PS (GlaFII-PS) or in PS deleted of the thrombin-sensitive region (TSR) (GlaFII-TSR-PS). Both PS/FII chimeras had no APC-cofactor activity in plasma clotting assays or purified systems, but bound efficiently to phospholipids. This pointed to a direct involvement of the PS Gla domain in APC-cofactor activity, through molecular interaction with APC. Using computational methods, we identified two opposite faces of solvent-exposed residues on the PS Gla domain (designated Faces 1 and 2) as being potentially involved in this interaction. Their importance was supported by functional characterization of a PS mutant in which the Faces 1 and 2 PS residues were reintroduced into GlaFII-PS, leading to significant APC-cofactor activity, likely via restored interaction with APC. Furthermore, by characterizing PS mutants in which PS Face 1 and PS Face 2 were individually replaced by the corresponding prothrombin faces, we found that Face 1 was necessary for efficient phospholipid binding, while Face 2 residues were not strictly required for phospholipid binding but were involved in the interaction with APC. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Gla glances at proteins Tilman M. Hackeng Blood 2005 105: 1-2. [Full Text] [PDF] This article has been cited by other articles: S. Harmon, R. J. S. Preston, F. N. Ainle, J. A. Johnson, M. S. Cunningham, O. P. Smith, B. White, and J. S. O'Donnell Dissociation of Activated Protein C Functions by Elimination of Protein S Cofactor Enhancement J. Biol. Chem., November 7, 2008; 283(45): 30531 - 30539. [Abstract] [Full Text] [PDF] B. Saposnik, E. Lesteven, A. Lokajczyk, C. T. Esmon, M. Aiach, and S. Gandrille Alternative mRNA is favored by the A3 haplotype of the EPCR gene PROCR and generates a novel soluble form of EPCR in plasma Blood, April 1, 2008; 111(7): 3442 - 3451. [Abstract] [Full Text] [PDF] R. J. S. Preston, E. Ajzner, C. Razzari, S. Karageorgi, S. Dua, B. Dahlback, and D. A. Lane Multifunctional Specificity of the Protein C/Activated Protein C Gla Domain J. Biol. Chem., September 29, 2006; 281(39): 28850 - 28857. [Abstract] [Full Text] [PDF] B. Dahlback and B. O. Villoutreix Regulation of Blood Coagulation by the Protein C Anticoagulant Pathway: Novel Insights Into Structure-Function Relationships and Molecular Recognition Arterioscler Thromb Vasc Biol, July 1, 2005; 25(7): 1311 - 1320. [Abstract] [Full Text] [PDF]

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