Relating structure to function: the role of the C2 domain in Factor VIII.

Factor VIII is a plasma glycoprotein that becomes activated during blood coagulation. Through its association with other procoagulant components at the wound site, it leads to a tremendous acceleration in the production of thrombin, and thus to the rate at which bleeding is staunched. Deficiencies in Factor VIII can result in hemophilia A, the most common hereditary bleeding disorder. Advances in molecular biology and protein chemistry led to characterization of Factor VIII and its gene in the early 1980s. Over the past 15 years, PCR methods combined with careful clinical studies have identified many of the molecular defects associated with hemophilia A. Concurrently, basic research utilizing both plasma-derived Factor VIII and recombinant constructs has led to a greatly improved understanding of the functions of specific regions within this large glycoprotein. This review focuses on recent advances in elucidating the roles of the Factor VIII carboxy terminal C2 domain. Particular emphasis is placed upon interpreting biophysical measurements and clinical data in light of the recently obtained high-resolution crystal structure of the recombinant C2 domain. Some interesting directions for future experiments are also suggested.