Research TopicsDepartment of Biochemistry, College of Medicine
Ph.D. (1980) University of California
Research Topics
- Membrane-bound proteases
- Modulation of serine protease function
- Control of the blood clotting system
Research Interests
Modulation of protease function by protein cofactors represents a key regulatory feature of activation cascades in a variety of biological systems. Although much has been learned in recent years about the structure/function relationship of serine proteases, far less is known about how protein cofactors--and phospholipid membranes-modulate serine protease function. Our laboratory is studying the assembly of protease complexes on membrane surfaces that control the blood clotting cascade. Tissue factor, an integral membrane protein, serves as the cell-surface receptor for the plasma serine protease, factor VIIa. Binding of factor VIIa to tissue factor converts factor VIIa for a very weak protease to a highly active protease. The resulting tissue factor/factor VIIa complex triggers the blood clotting system in both normal hemostatsis and many thrombotic diseases. Since thrombosis represents the major cause of disability and death worldwide, understanding how these cell-surface protease complexes assemble and function is of substantial medical importance
We are currently studying the detailed effects of tissue factor binding on the enzymatic activity of factor VIIa, using site-directed mutagenesis as well as protein fluorescence approaches. These studies also include structure/function studies of the known protein substrates for this enzyme/cofactor complex (coagulation factors V, VIII, IX and X). In addition, we are investigating the very important, but not well understood, role of the phospholipid membrane in catalysis. These studies have serendipitously allowed us to develop novel clinical assays for potential risk factors for heart disease and other thrombotic disorders, which we are pursuing in collaborative studies with clinical investigators.
Key Words Recombinant DNA, Gene Expression Systems, Protein-Protein
Interactions, Site-Directed Mutagenesis, Membrane Structure and Function,
Protein Purification and Characterization, Active Sites and Receptors,
Diagnostic Reagents
Current Research Funding NIH (NHLBI)