The Gla²⁶ Residue of Protein C Is Required for the Binding of Protein C to Thrombomodulin and Endothelial Cell Protein C Receptor, but not to Protein S and Factor Va

Summary

A functionally defective protein C (PC)-Mie, detected in the plasma of a patient with hereditary thrombophilia, has Lys substituted for γ-carboxyglutamic acid (Gla)²⁶ residue. The activation rate of PC-Mie by Protac or thrombin in the absence of Ca²⁺ and that by thrombin with native thrombomodulin (TM), recombinant soluble truncated TM or on cultured endothelial cells in the presence of Ca²⁺ were all apparently lower than that of normal PC. The anticoagulant activity of Protac-activated PC (APC)-Mie on the plasma clotting time and the rate of inactivation of factor Va by APC-Mie in the presence of phospholipids were lower than those seen with normal APC. APC-Mie and normal APC bound equally to protein S and to biotinyl-factor Va. However, neither PC-Mie nor APC-Mie bound to phospholipids and to cultured human endothelial cells. It was similar to that observed with Gla-domainless PC/APC, but different from that seen with normal PC/APC. These results suggest that Gla²⁶-dependent conformation is required for the binding of PC/APC to phospholipids, TM and the surface of endothelial cell PC/APC receptor, but not to protein S and factor Va.

• References

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