Search

The cell surface receptor tissue factor (TF) binds to the serine protease coagulation factor VIIa. The binding sites are present from TF's concave side of the elbow angle at the module boundary to the convex side of the amino-terminal module at the edge of the three- and four-stranded beta-sheet. These ligand binding sites contribute one-third of the energy required for binding, while additional energy is contributed by the residues on the convex surface of the amino-terminal module.

A study of residue side chains reveals that the tissue factor extracellular domain possibly adopts the cytokine receptor homology unit folding pattern with two seven-beta-strand modules. Mutational analysis suggests that important residues are spatially closer and present as a cluster on the beta-strand module boundary. Residues involved in ligand binding occur in positions corresponding to ligand interactive residues.

A combinatorial library derived peptide, which binds to the extracellular domain of tissue factor, exhibits selective and quantitatively limited attenuation of factor X and the extrinsic limb of the coagulation protease cascades. Data indicate that such peptides provide attenuation of thrombotic risk on a long-term basis.

Macromolecular substrate docking that involves coagulation enzyme-cofactor complexes typically requires multiple contacts distant from an enzyme's catalytic cleft. To illustrate the role of the VIIa Gla-domain in macromolecular substrate docking, a group of site-directed mutants of this domain were generated and characterized. Analysis reveals that specific residues of the VIIa Gla-domain have a critical role in the activation of the macromolecular substrate factor X, one that is dependent on the Gla domain of the substrate being properly folded.