lant systems are in place to tightly regulate coagulation. An important system is represented by the protein C anticoagulant pathway, whose roles beyond the control of coagulation are emerging. The anticoagulant actions prevent thrombosis while the more recently discovered cytoprotective actions prevent vascular damage and stress.
Proteolytic activation of protein C (Proc) is carried out by thrombin/F2 bound to the membrane receptor thrombomodulin (Thbd). F2 is the last protease of the coagulation cascade; its binding to Thbd obscures the procoagulant site - exosite 1, converting it to an anticoagulant factor. Binding of protein C to its receptor, Procr, anchors it to the endothelial surface, allowing for its presentation to the thrombin-thrombomodulin complex and subsequent activation. As an anticoagulant, activated protein C (Proc_act) dissociates from Procr (Proc_act_diss) and, assisted by protein S cofactor, effectively inactivates coagulation cofactors 5a and 8a. F8a is the cofactor for coagulation factor 9a in the 'tenase complex'; F5a is the cofactor for coagulation factor 10a in the 'thrombinase complex'. Both protein C and protein S cofactor are vitamin K-dependent (VKD) proteins. Vitamin K serves as a cofactor in the reaction that modifies specific glutamine (Glu) residues to gamma-carboxyglutamate (Gla) residues. Glas (10 to 12) in the amino terminal Gla domain (click to access the PFAM entry) mediate the reversible, calcium-dependent binding to negatively charged phospholipids (phosphatidylserine or phosphatidic acid) of membranes. With each modified residue, a reduced form of vitamin K is oxidized and is then converted back, to provide the necessary cofactor for the next reaction - the metabolic pathway is known as the vitamin K cycle. Also VKD proteins are the coagulation factors F2, F7, F9 and F10, and several other proteins. The localization of coagulation factors and regulators of coagulation at/near sites of vascular injury is crucial for proper hemostatic function.

In a different role, Proc_act bound to Epcr prompts cytoprotective actions via activation of protease-activated receptors (PARs). PARs are G protein-coupled receptors (GPCR) involved in many responses and can elicit distinct downstream events depending on the identity of the protease and cellular environment; the alternative outcomes are referred to as 'biased signaling'. Of the four members, primarily Par1/F2R, but also Par3/F2Rl2, are targets. These receptors are also targets of thrombin/F2; however, the effects elicited by Proc and F2 are not only different, they are divergent. Cytoprotective effects elicited by Proc-Epcr include antiapoptotic, anti-inflammatory and endothelial barrier stabilization. In contrast, thrombin-elicited effects are pro-inflammatory and barrier destabilizing. The alternative outcomes - 'biased signaling', result from cleavage of receptors at different sites by different proteases, yielding new, and distinct N-terminal tethered agonists, associated conformations and allosteric modulations, as well as distinct conformations receptors can have in the membrane environment. The Proc cleavage site in Par1 is different from the 'canonical' cleavage site of thrombin.

Given the many roles Proc in association with its receptor/cofactor can play, alterations in protein C pathway can have profound negative consequences. To see the ontology report for annotations, GViewer, and download, click here...(less)