Edward Pryzdial,

• Blood Proteins
• Coagulation and Fibrinolysis
• Role of Blood Proteins in Viral Infection

General Research Interest
The general expertise in our laboratory is the function of blood proteins. By combining biochemistry and molecular engineering to understand parts of molecules, we have discovered novel functions of several proteins with possible therapeutic or diagnostic applications to heart disease and virus infection. Using state-of-the-art proteomics technologies, our long-range goal is to understand how these findings may impact on other blood protein functions and thereby contribute to optimizing the value derived from blood constituents and their substitutes.

Communication Between Clot-Forming and Clot-Dissolving Proteins Clot generation (coagulation) and subsequent dissolution (fibrinolysis) are fundamental biological processes. A high degree of communication between these opposing pathways is necessary to ensure that clots form and are localized only where they are needed. The biological effector of coagulation, thrombin, is generated by an enzyme complex consisting of the serine protease factor Xa (FXa), the cofactor Va (FVa) and anionic phospholipid, together termed prothrombinase. In recent work, we identified a previously unknown mechanism of communication between prothrombinase and the fibrinolysis pathway. The data revealed that FXa and FVa accelerate the production of the fibrinolysis protease plasmin, through a feedback-controlled mechanism. At the same time, plasmin irreversibly inhibits the coagulation activity of prothrombinase. Studies are being conducted to further understand how these newly discovered functions may contribute to normal clot production.

Blood Proteins Exploited by Viruses For decades certain viruses have been linked to heart disease. To understand the molecular basis for the clinical correlation, we have found that at least cytomegalovirus, herpes simplex virus type 1 and type 2, can directly activate and assemble clotting protein complexes to generate thrombin. The aberrant initiation of clot formation by viruses is a double-edged pathological sword. Not only may it contribute to heart disease, but it may also have evolved to enhance the susceptibility of host cell infection. At least for cytomegalovirus, we have recently implicated thrombin-Mediated exposure of a blood cell protein, called annexin 2, in virus cell-entry. We are now dissecting the specific mechanisms on the virus surface that initiate coagulation and the role of thrombin in virus propagation.

Selected Publications:

Song, J., Talbot, K., Hewitt, J., MacGillivray, R.T.A. and Pryzdial, E.L.G. (2009) Differential contribution of Glu96, Asp102 and Asp111 to coagulation factor Va metal ion binding and subunit stability. Biochemical Journal 422:257-264

Sutherland, M.R., Friedman, H.M. and Pryzdial, E.L.G. (2007) Thrombin production initiated by herpes simplex virus increases infection of cells through protease activated receptor 1. Journal of Thrombosis and Haemostasis Journal of Thrombosis and Haemostasis 5:1055-1061

Derry, M.C., Sutherland, M.R., Restall, C.M., Waisman, D.M. and Pryzdial, E.L.G. (2007) Annexin 2-mediated enhancement of cytomegalovirus infection opposes inhibition by annexin 1 or annexin 5. Journal of General Virology 88:19-27

Livingston, J.R., Sutherland, M.R., Friedman, H.M. and Pryzdial, E.L.G. (2006) Herpes simplex virus type 1-encoded glycoprotein C contributes to direct coagulation factor X-virus binding. Biochemical Journal 393: 529-535

Grundy, J., Hirama, T., MacKenzie, R. and Pryzdial, E.L.G. (2001) Binding of plasminogen and tissue plasminogen activator to plasmin-modulated coagulation factors X and Xa. Biochemistry 40:6293-6302