Coagulation factor VIII precursor
Homo sapiens (human)
Hemophilia is an illness characterized by the inability to stop bleeding. It is caused by the lack or deficiency of one of the coagulation factors, proteins in blood that cause blood clotting. It is an inherited disease, not an acquired one. The most predominant type of hemophilia, classic or hemophilia A, is caused by a deficiency of factor VIII protein. About 80% of all cases of hemophilia belong to this class. Hemophilia A can be treated by infusion with factor VIII to supplement the natural deficiency. Unfortunately many hemophiliacs develop antibodies against factor VIII that inhibit its activity. Factor VIII is usually present in the blood as a complex with another protein, the so-called von Willebrandt factor (vWF). Factor VIIIa, created from factor VIII by cleavage with thrombin, combines with activated factor IXa and this complex activates factor X, the factor where the intrinsic and extrinsic blood coagulation pathways merge. Factor Xa then activates thrombin and initiates the final steps of blood clotting.
The structure here shows one part of factor VIII, the C2 domain toward the carboxyl-terminal end of the whole protein. This part of factor VIII is responsible both for the interaction with the von Willebrandt factor and with the cell surface membranes. Mutations, changes in amino acid sequence in this part are responsible for reduced interactions. It is therefore of great interest to understand the structure and the changes caused by mutations. Factor VIII that is not associated with the von Willebrandt factor, is eliminated from the blood more readily and thus leads to factor VIII deficiency. Understanding all these interactions may help to design ways for improved treatment of hemophilia A.
Protein Data Bank (PDB)
Pratt, K.P. Shen, B.W. Takeshima, K. Davie, E.W. Fujikawa, K. Stoddard, B.L.; "Structure of the C2 domain of human factor VIII at 1.5 Angstroms resolution."; Nature; (1999) 402:439-442 PubMed:10586887.
author: Arno Paehler