Blood coagulation derives from a series of specific proteolytic activation reactions that are catalyzed with narrow and defined specificity by trypsin-like serine proteinases. In several instances, these proteinases function in membrane assembled enzyme complexes. Distinctive protein substrate specificities and the modulation of enzymic function by interactions with membranes and cofactors are hallmarks of the proteolytic reactions of blood coagulation. There are major gaps in the current understanding in the molecular bases for these unique features that underlie the function of the coagulation reactions. This program proposes and integrated approach focused on the contributions of macromolecular interactions to the specificity and modulation of enzymic function that leads to action of the hemostatic enzymes. Project 1 (Krishnaswamy) uses the prothrombinase complex as a paradigm to investigate the role of extended macromolecular interactions between the protein substrate and the enzyme complex in explaining protein substrate specificity and cofactor function. Project 2 (Camire) will investigate the relationship between zymogen proteolysis and the development of discrete macromolecular binding interactions that lead to the assembly of the prothrombinase complex and the expression of enzymic function. Studies are also proposed to assess the role of cofactor-substrate interactions in determining function. Project 3 (Zheng) investigates the link between coagulation and von Willebrand Factor processing by investigating the regulation of ADAMTS13 function by factor VIII and shear stress. The objectives of the three projects will be supported by an administrative core and a core that provides support for molecular biology and protein expression. Overall, this project applies the expertise of the individual investigators towards addressing major unanswered questions in hemostasis. The proposed approaches will provide new insights into the chemistry and biology of the blood coagulation reactions with implications for an understanding of normal hemostasis and thrombosis. Aberrations in the blood clotting system can lead to too much bleeding or excessive clotting. Disorders in the clotting process represent a major cause of disease and death in humans. This program seeks to develop new information by which key reactions of blood clotting are regulated. This information will lead to new concepts and strategies for the treatment of blood clotting-related human disease.
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