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

Ahnström, JosefinLund University,Lunds universitet,Klinisk kemi, Malmö,Forskargrupper vid Lunds universitet,Clinical Chemistry, Malmö,Lund University Research Groups (författare)

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)

Andersson, Helena (författare)
Canis, Kevin (författare)
Norström, EvaLund University,Lunds universitet,Klinisk kemi, Malmö,Forskargrupper vid Lunds universitet,Clinical Chemistry, Malmö,Lund University Research Groups(Swepub:lu)klke-eno (författare)
Yu, Yao (författare)
Dahlbäck, BjörnLund University,Lunds universitet,Klinisk kemi, Malmö,Forskargrupper vid Lunds universitet,Clinical Chemistry, Malmö,Lund University Research Groups(Swepub:lu)klke-bda (författare)
Panico, Maria (författare)
Morris, Howard R. (författare)
Crawley, James T. B. (författare)
Lane, David A. (författare)
Klinisk kemi, MalmöForskargrupper vid Lunds universitet (creator_code:org_t)

Ingår i:Blood: American Society of Hematology117:24, s. 6685-66931528-00200006-4971

Av författaren/redakt...: Ahnström, Josefi ...; Andersson, Helen ...; Canis, Kevin; Norström, Eva; Yu, Yao; Dahlbäck, Björn; visa fler...; Panico, Maria; Morris, Howard R ...; Crawley, James T ...; Lane, David A.; visa färre...

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