Principal Investigator
Research Projects
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Mechanisms for the Proteolytic Activation of Factor VIII
Proteolytic activation of factor VIII is required to generate the active cofactor. Thrombin catalyzes cleavage at the three scissile bonds in factor VIII by an exosite-dependent mechanism. We are working towards defining a model for this mechanism following binding interactions using factor VIII chains and factor VIIIa subunits, as well as variant proteins constructed with point mutations at potentially critical exosite-interactive regions. More info...
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Interactions Between A2 Subunit and the A1/A3C1C2 Dimer in Factor VIIIa
Activation of the factor VIII procofactor results in structural changes that likely impact orientation of the A2 domain in factor VIIIa, since this subunit contacts the protease domain of factor IXa in Xase directly stimulating catalysis. Furthermore, A2 subunit dissociation represents the primary mechanism for factor VIIIa inactivation and subsequent dampening of factor Xase. More info...
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Intermolecular Interactions in Factor Xase Assembly and Function
Relatively little detailed information exists related to assembly of factor VIIIa into the Xase complex or mechanisms by which factor VIIIa enhances the kcat of factor IXa by several orders of magnitude. We are addressing significant issues related to intermolecular interactions of factor VIIIa in factor Xase assembly and function. More info...
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Proteolytic Inactivation of Factor VIIIa and Down-Regulation of Factor Xase
Examination of the proteolytic inactivation of factor VIIIa is based in part upon our recent studies showing significant contributions of sequences flanking the P1 Arg residues in activated protein C (APC)- and factor Xa-catalyzed inactivation of factor VIIIa, as well as earlier work in localizing binding sites for APC on the cofactor. Recent preliminary data by SPR suggest contributions of both factor VIII heavy and light chain-derived subunits to form a binding site for APC. More info...
