Structure/function of the fourth and fifth EGF domains of thrombomodulin

Abstract

This chapter discusses about the structure and function of the essential epidermal growth factor (EGF)-like domains of human thrombomodulin (TM). Both the fourth and fifth domains are necessary and sufficient for TM cofactor activity. The fragment of TM containing only the fifth and sixth EGF-like domains binds to thrombin, but has no cofactor activity. The fifth domain alone inhibits thrombin-induced clotting of fibrinogen and activation of protein C by the thrombin-TM complex, both indicators of thrombin-binding. The results suggest that the fifth domain may bind to thrombin by an induced fit mechanism. However, the fourth domain shows no thrombin binding activity or TM cofactor activity. The fourth domain is rigid and unable to bind without the fifth, and the fifth has non-EGF-like disulfide bonds that give it the flexibility to bind thrombin by an induced fit mechanism. Thus the fourth and fifth domains function together.