Exosite crosstalk in thrombin.

Abstract

Thrombin is the central mediator of hemostasis, where it converts fibrinogen to fibrin, activates upstream factors to promote coagulation, activates factor XIII and thrombin-activatable fibrinolysis inhibitor to stabilize fibrin, mediates anticoagulation, and modulates cellular activity via cell surface receptors. Thus, regulation of thrombin activity is essential to the hemostatic balance. Thrombin is regulated by positively charged surface domains that surround the active site. These exosites bind substrates, inhibitors, cofactors, and receptors that coordinate to direct thrombin to the appropriate location and modulate catalytic activity. Thus, the exosites are essential to the activity and regulation of thrombin. In addition to acting as binding sites, the exosites modulate the active site allosterically. Furthermore, the exosites impact each other, whereby the binding of ligands to one exosite impacts the function of the opposing exosite. Given the integral role that exosites play in the regulation of thrombin, they are attractive targets for the regulation of thrombin; they are attractive targets for the development of new anticoagulants.