Interactions of Fibrinogen Gamma' Variant with Thrombin

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DESCRIPTION (provided by applicant): My long-term goals are to define the interactions between the gamma variant form of fibrinogen and thrombin. The specific aims of this proposal are to: I- Map the Ca2+ binding site(s) on the gamma chain. The hypothesis to be tested is that the gamma chain provides an additional Ca2+ binding site(s) in fbrinogen.II - Determine the effect of the gamma chain on thrombin's enzymatic activity towards protein substrates. The hypothesis to be tested is that the gamma chain modulates thrombin cleavage of substrates by binding to exosite II. III- Determine the effect of the gamma chain on thrombin inhibition by protease inhibitors. The hypothesis to be tested is that a plasmin cleavage product of the gamma chain catalyzes thrombin inhibition by heparin-dependent inhibitors, and that the gamma chain binds to heparin-dependent inhibitors. IV- Determine the effect of the gamma chain on thrombin's procoagulant activity and platelet aggregating activity in whole plasma. The hypothesis to be tested is that a plasmin cleavage product of the gamma chain acts as an anticoagulant in plasma.