STRUCTURE OF THE EXTRACELLULAR DOMAIN OF HUMAN TISSUE FACTOR - LOCATION OF THE FACTOR VIIA BINDING-SITE

Tissue factor, the obligate cofactor for coagulation factor VII, plays an essential role in hemostasis by initiating the extrinsic pathway o f blood coagulation upon vascular damage, making it a promising target for new anticoagulant therapies in the treatment of thrombosis and se psis. The three-dimensional structure of the extracellular domain of t issue factor, determined by X-ray crystallography at a resolution of 2 .4 Angstrom, consists of two domains of approximately equal size, with a topology characteristic of fibronectin type III modules. Comparison of tissue factor with the extracellular domain of the growth hormone receptor, which belongs to the same receptor superfamily, shows that t he relative orientation between these domains as well as the domain-do main interface is very different. These differences have dramatic cons equences for the residues in tissue factor that are homologous to the binding determinants of the growth hormone receptor. Alanine-scanning mutagenesis has identified tissue factor residues important for factor VIIa binding. The structure shows that the binding site is located in the domain-domain interface region but on the opposite side of the mo lecule compared to the growth hormone receptor, with the binding deter minants residing on beta-strands rather than on loops.