Human FactorVIII

Abstract Factor VIII is a critical blood clotting factor, which forms a complex with the serine protease factor IXa upon activation to convert factor X to factor Xa, which in turn activates thrombin. Deficiency or dysfunction of the protein leads to hemophilia A, a common X‐linked disorder. Structures of two different constructs of factor VIII have been determined by X‐ray crystallography at intermediate resolutions. Both structures show that the protein is composed of five globular domains and contains binding sites for calcium and copper ions, which are important in the regulation of factor VIII structure and activity. The three A domains, each consists of two β‐barrel structures that resemble the cupredoxin fold, are structurally homologous with one other. The two homologous C domains are defined by a distorted β‐barrel and reveal membrane‐binding features. Comparison of the two crystal structures has revealed structural differences between the two constructs and provides new perspectives for understanding the activation of factor VIII and the role of metal ions in the regulation of factor VIII activity.