Molecular interaction between factor VII and tissue factor.

Abstract

Complex formation between serine protease factor VIIa (VIIa) and tissue factor (TF) dramatically enhances the catalytic activity of VIIa, leading to the initiation of extrinsic blood coagulation. The recently determined crystal structure of the complex formed between VIIa and the extracellular domain of TF has revealed in detail the interacting surfaces of the two molecules. Mutational and biochemical studies have further identified regions of VIIa and/or those of TF essential for the high affinity interaction. These studies indicate that the regions extending from the gamma-carboxyglutamic acid domain through the first epidermal growth factor-like domain and protease domain of VIIa are involved separately in the interaction with the distinct sites of TF. The interaction of TF with the protease domain of VIIa apparently induces a conformational transition of the VIIa active site. Studies of the chemical modification of VIIa provided a model for the mechanism of TF-mediated acceleration of VIIa activity. In this model, the protease domain of VIIa exists in equilibrium between minor active and dominant zymogen-like inactive conformational states, and preferential binding of TF to the active state leads to a shift in equilibrium into the active state, thereby accelerating VIIa activity. Overall docking of TF with VIIa in the presence of phospholipids further supports a recognition of macromolecular substrates, such as factors IX and X. Therefore, single VIIa-TF interaction contains several distinct mechanisms for enhancing the coagulant activity of VIIa, which may be important for the initiation of coagulation specifically mediated by TF. Studies of the interaction between VIIa and TF provide not only a detailed understanding of the regulated initiation of blood coagulation but also the potential to design novel anticoagulants for the treatment of thrombotic diseases.