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

Ahnström, Josefin (author)
Lund University,Lunds universitet,Klinisk kemi, Malmö,Forskargrupper vid Lunds universitet,Clinical Chemistry, Malmö,Lund University Research Groups
Andersson, Helena (author)
Canis, Kevin (author)
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Norström, Eva (author)
Lund University,Lunds universitet,Klinisk kemi, Malmö,Forskargrupper vid Lunds universitet,Clinical Chemistry, Malmö,Lund University Research Groups
Yu, Yao (author)
Dahlbäck, Björn (author)
Lund University,Lunds universitet,Klinisk kemi, Malmö,Forskargrupper vid Lunds universitet,Clinical Chemistry, Malmö,Lund University Research Groups
Panico, Maria (author)
Morris, Howard R. (author)
Crawley, James T. B. (author)
Lane, David A. (author)
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 (creator_code:org_t)
American Society of Hematology, 2011
2011
English.
In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 117:24, s. 6685-6693
  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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)

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Hematologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Hematology (hsv//eng)

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