Molecular Models for the two Discoidin Domains of Human Blood Coagulation Factor V

Abstract

Discoidin (DS) domains occur in a large variety of proteins. We have recently reported the D1 domain of galactose oxidase (GOase), a copper-containing enzyme whose structure has been determined at 1.7 A resolution, as distant member of the DS domain family. The D1 domain of GOase consists of a five-stranded antiparallel β-sheet packing against a three-stranded antiparallel β-sheet. We here show that it is possible to build 3D models for DS domains using GOase as initial template and propose a 3D structure for the C1 and C2 domains of factor V (residues 1879-2037 and 2038-2196). Factors V (FV) and VIII (FVIII) are essential and homologous non-enzymatic cofactors in the coagulation cascade. They share the domain organization A1-A2-B-A3-C1 and C2 and their C domains are members of the DS family. The C1 and C2 domains of FV are rich in positively charged residues. Several clusters of amino acids, most likely involved in inter-domain interactions, protein-protein interactions and/or phospholipid binding, are identified. Our report opens new avenues to study the structure-function relationships of DS domains.