The fibrinogen sequences that interact with thrombin.

HE SERINE PROTEASE thrombin interacts with a T variety of substrates and as a consequence is involved in a number of physiologic processes. Fibrinogen is a particularly interesting substrate of thrombin for a number of reasons. First, thrombin cleaves not just one but four peptide bonds in fibrinogen, apparently in four successive steps. As a result ofthese proteolytic cleavages, the soluble fibrinogen molecules are converted into an insoluble fibrous polymer. In addition, the affinity of the enzyme for the final product, fibrin, is similar to that for the substrate, fibrinogen. Active thrombin is thus bound by the fibrin clot in a form largely resistant to inactivation by thrombin inhibitors, a situation that has important clinical consequences and complicates clinical anticoagulant therapy. This review focuses on the specific sequences of fibrinogen and fibrin that interact with thrombin. As illustrated in recent x-ray crystal structures of thrombin, the thrombin active site can be considered as two separate domains: a catalytic site that includes the Asp-His-Ser catalytic residues, the specificity pocket and an apolar pocket; and an extended fibrinogen recognition site (FRS). '3' The fibrin(ogen) regions responsible for binding to the catalytic site and the FRS will be examined and the properties of fibrin-bound thrombin discussed.