Philip J. Fay, Ph.D.

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Factor VIII serves as a protein cofactor for the serine protease, factor IXa in the surface-dependent conversion of factor X to factor Xa during the blood coagulation cascade reactions. Deficiency or defects in factor VIII result in hemophilia A, the most common of the severe, inherited bleeding disorders. Ongoing studies in our laboratory include physical and biochemical analyses of factor VIII structure and inter-subunit interactions. We are particularly interested in study of the activated form of the cofactor, factor VIIIa, which consists of a labile heterotrimeric structure. Additional studies assess functional changes reflecting altered structure following interaction of factor VIII/factor VIIIa with effector molecules (serine proteases) such as thrombin and activated protein C.

The role of factor VIIIa is to increase the kcat of factor IXa by several orders of magnitude. Little is known about the mechanism by which this is achieved. A second major focus of our lab is to elucidate the molecular basis for the cofactor effect following reconstitution of the intrinsic factor Xase complex (factor IXa, factor VIIIa (or isolated subunits) plus phospholipid vesicles) using purified components.

These projects are complemented by the generation and analysis of recombinant proteins possessing point mutations at sites proposed to contribute to intra- and inter-protein interactions. Overall, our research program is aimed at gaining fundamental insights into the structure, activity and regulation of a protein central to hemostasis.

Current Appointments

• Professor - Department of Biochemistry and Biophysics (SMD)

Education
PhD Biochemistry	Univ Rochester Sch Med/Dent	1982
MS Molecular Biology	SUNY Coll at Buffalo	1977
BS Microbiology	Ohio State Univ-Mansfield	1975

Recent Journal Articles
Showing the 5 most recent journal articles. (111 available)
Newell, J. L.; Fay, P. J.;. "Cleavage at Arg-1689 influences heavy chain cleavages during thrombin-catalyzed activation of factor VIII". J Biol Chem 284 (2009): 11080-9.
Wakabayashi, H.; Griffiths, A. E.; Fay, P. J.;. "Combining mutations of charged residues at the A2 domain interface enhances factor VIII stability over single point mutations". J Thromb Haemost 7 (2009): 438-44.
Wakabayashi, H.; Fay, P. J.;. "Identification of Residues Contributing to A2 Domain-dependent Structural Stability in Factor VIII and Factor VIIIa". J Biol Chem 283 (2008): 11645-51.
Newell, J. L.; Fay, P. J.;. "Acidic residues C-terminal to the A2 domain facilitate thrombin-catalyzed activation of factor VIII". Biochemistry 47 (2008): 8786-95.
Wakabayashi, H.; Varfaj, F.; Deangelis, J.; Fay, P. J.;. "Generation of enhanced stability factor VIII variants by replacement of charged residues at the A2 domain interface". Blood 112 (2008): 2761-9.