Date of Award

2009

Degree Type

Dissertation

Department

Chemistry

First Advisor

Kalafatis, Michael

Subject Headings

Thrombin, Prothrombin, Blood coagulation factors, Factor Va, Thrombin, Prothrombinase

Abstract

The LONG-TERM goal of our research is to study and analyze the structure and function of the factor V molecule in order to understand its regulatory effects on the natural process of hemostasis and its role in the life-threatening development of deep venous thrombosis. The SHORT-TERM goal of our research is to identify the amino acid residue(s) of factor V that interact with prothrombin during the assembly and function of the prothrombinase complex in order to fully understand its particular role in maintaining the integrity of the blood coagulation cascade. The final goal of the coagulation cascade is the formation of a fibrin clot that is catalyzed by the serine protease, thrombin. The proteolytic conversion of prothrombin to thrombin is catalyzed by the prothrombinase complex composed of the enzyme, factor Xa, its cofactor, factor Va, assembled on a membrane surface in the presence of divalent metal ions. Although factor Xa alone can activate prothrombin, it is at a rate that is not compatible for survival. Incorporation of factor Va into the prothrombinase complex results in a 300,000-fold increase in the catalytic efficiency of factor Xa for thrombin generation and plays an important role in regulating prothrombin activation. Thus, it is crucial to identify which specific amino acid residue(s) are responsible for the interaction of factor Va with prothombin and factor Xa in the formation of thrombin, which is absolutely vital for maintaining normal hemostasis in a healthy individual. The specific aims of the present study are To identify the specific amino acid region of the factor Va heavy chain that promotes optimal cofactor function during prothrombin activation To identify key acidic amino acid sequences in the factor Va molecule that control the rate of prothrombin cleavage To identify the specific amino acids of the factor V/Va heavy chain that regulate enzyme-substrate interaction during prothrombin activation

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