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Activated protein C cofactor function of protein S: a novel role for a gamma-carboxyglutamic acid residue

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Author

  • Josefin Ahnström
  • Helena Andersson
  • Kevin Canis
  • Eva Norström
  • Yao Yu
  • Björn Dahlbäck
  • Maria Panico
  • Howard R. Morris
  • James T. B. Crawley
  • David A. Lane

Summary, in English

Protein S has an important anticoagulant function by acting as a cofactor for activated protein C (APC). We recently reported that the EGF1 domain residue Asp95 is critical for APC cofactor function. In the present study, we examined whether additional interaction sites within the Gla domain of protein S might contribute to its APC cofactor function. We examined 4 residues, composing the previously reported "Face1" (N33S/P35T/E36A/Y39V) variant, as single point substitutions. Of these protein S variants, protein S E36A was found to be almost completely inactive using calibrated automated thrombography. In factor Va inactivation assays, protein S E36A had 89% reduced cofactor activity compared with wild-type protein S and was almost completely inactive in factor VIIIa inactivation; phospholipid binding was, however, normal. Glu36 lies outside the omega-loop that mediates Ca2+-dependent phospholipid binding. Using mass spectrometry, it was nevertheless confirmed that Glu36 is gamma-carboxylated. Our finding that Gla36 is important for APC cofactor function, but not for phospholipid binding, defines a novel function (other than Ca2+ coordination/phospholipid binding) for a Gla residue in vitamin K-dependent proteins. It also suggests that residues within the Gla and EGF1 domains of protein S act cooperatively for its APC cofactor function. (Blood. 2011;117(24):6685-6693)

Publishing year

2011

Language

English

Pages

6685-6693

Publication/Series

Blood

Volume

117

Issue

24

Document type

Journal article

Publisher

American Society of Hematology

Topic

  • Hematology

Status

Published

Research group

  • Clinical Chemistry, Malmö

ISBN/ISSN/Other

  • ISSN: 1528-0020