Molecular recognition in the protein C anticoagulant pathway

Abstract

The protein C (PC) anticoagulant system provides specific and efficient control of blood coagulation. The system comprises circulating or membrane-bound protein components that take part in complicated multimolecular protein complexes being assembled on specific cellular phospholipid membranes. Each of the participating proteins is composed of multiple domains, many of which are known at the level of their three-dimensional structures. The key component of the PC system, the vitamin K-dependent PC, circulates in blood as zymogen to an anticoagulant serine protease. Activation is achieved on the surface of endothelial cells by thrombin bound to the membrane protein thrombomodulin. The endothelial PC receptor binds the Gla domain of PC and stimulates the activation. Activated PC (APC) modulates the activity of blood coagulation by specific proteolytic cleavages of a limited number of peptide bonds in factor (F)VIIIa and FVa, cofactors in the activation of FX and prothrombin, respectively. These reactions occur on the surface of negatively charged phospholipid membranes and are stimulated by the vitamin K-dependent protein S. Regulation of FVIIIa activity by APC is stimulated not only by protein S but also by FV, which, like thrombin, is a Janus-faced protein with both pro- and anticoagulant potential. However, whereas the properties of thrombin are modulated by protein-protein interactions, the specificity of FV function is governed by proteolysis by pro- or anti-coagulant enzymes. The molecular recognition of the PC system is beginning to be unravelled and provides insights into a fascinating and intricate molecular scenario.