This program project application represents a renewal of a coordinated multi-laboratory investigation of the synthesis of g-carboxyglutamic acid in the membrane binding Gla domain of the vitamin K-dependent blood clotting proteins and the mechanism by which blood clotting proteins assemble on membrane surfaces. The program has involved collaborations among five laboratories, with most of the activities focused at the Center for Hemostasis and Thrombosis Research at the Beth Israel Deaconess Medical Center/Harvard Medical School. Dr. Barbara C. Furlie is the Director of the Program and Dr. Bruce Furie is the co-Director. The first project (Structure-Function of the g-glutamyl carboxylase; Dr. Barbara C. Furie and Dr. Christopher Walsh) will explore the structure and function of the carboxylase. With suitable, homogeneous quantities of the vitamin K-dependent carboxylase available for biochemical analysis, the proposed project will elucidate important aspects of carboxylase mechanism, carboxylase structure-function relationships and in vivo tissue-specific functions of carboxylase using a carboxylase null mouse model. Embryonic Synthesis and Function of g-Carboxyglutamate; Dr. David Roth defines the mechanisms underlying the regulation of Gla synthesis in developing and differentiated tissues, and provide insights into the pathogenesis of the warfarin embryopathy in studies of the transcriptional control of the carboxylase gene. The next project (Factor IX Complexes on Membrane Surfaces; Dr. Bruce Furie) will study the structure of Factor IX- membrane interaction and the structure of the Factor IXa-Factor VIIIa complex on membrane surfaces. The last project (Phospholipid Binding Structures of Factor VIII; Dr. Gary Gilber) will study the mechanism by which Factor VIII binds to membranes and the role of a peptide based upon the structure of Factor VIII to accelerate Factor X activation by Factor IXa.. The program includes three Core Units: an administrative core; an analytical core for synthesis of peptides and protein sequencing; a cell culture and animal core. The motivation for this program is to maintain an experienced interdisciplinary group to approach significant, challenging problems that are beyond the scope of a single investigator.
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