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Activated protein C cofactor function of protein S: a novel role for a γ-carboxyglutamic acid residue.
- Source :
-
Blood . 6/16/2011, Vol. 117 Issue 24, p6685-6693. 9p. - Publication Year :
- 2011
-
Abstract
- 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 ω-loop that mediates Ca2+-dependent phospholipid binding. Using mass spectrometry, it was nevertheless confirmed that Glu36 is γ-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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *PROTEIN S
*PROTEIN C
*PHOSPHOLIPIDS
*MASS spectrometry
*VITAMIN K
Subjects
Details
- Language :
- English
- ISSN :
- 00064971
- Volume :
- 117
- Issue :
- 24
- Database :
- Academic Search Index
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 66818351
- Full Text :
- https://doi.org/10.1182/blood-2010-11-317099