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Activated protein C cofactor function of protein S: a critical role for Asp95 in the EGF1-like domain

På svenska

Author

  • Helena M. Andersson
  • Marcia J. Arantes
  • James T. B. Crawley
  • Brenda M. Luken
  • Sinh Tran
  • Björn Dahlbäck
  • David A. Lane
  • Suely M. Rezende

Summary, in English

Protein S has an established role in the protein C anticoagulant pathway, where it enhances the factor Va (FVa) and factor VIIIa (FVIIIa) inactivating property of activated protein C (APC). Despite its physiological role and clinical importance, the molecular basis of its action is not fully understood. To clarify the mechanism of the protein S interaction with APC, we have constructed and expressed a library of composite or point variants of human protein S, with residue substitutions introduced into the Gla, thrombin-sensitive region (TSR), epidermal growth factor 1 (EGF1), and EGF2 domains. Cofactor activity for APC was evaluated by calibrated automated thrombography (CAT) using protein S-deficient plasma. Of 27 variants tested initially, only one, protein S D95A (within the EGF1 domain), was largely devoid of functional APC cofactor activity. Protein S D95A was, however, gamma-carboxylated and bound phospholipids with an apparent dissociation constant (Kd(app)) similar to that of wildtype (WT) protein S. In a purified assay using FVa R506Q/R679Q, purified protein S D95A was shown to have greatly reduced ability to enhance APC-induced cleavage of FVa Arg306. It is concluded that residue Asp95 within EGF1 is critical forAPC cofactor function of protein S and could define a principal functional interaction site for APC. (Blood. 2010;115(23):4878-4885)

Publishing year

2010

Language

English

Pages

4878-4885

Publication/Series

Blood

Volume

115

Issue

23

Document type

Journal article

Publisher

American Society of Hematology

Topic

  • Hematology

Status

Published

Research group

  • Clinical Chemistry, Malmö

ISBN/ISSN/Other

  • ISSN: 1528-0020