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Structure of the C2 domain of human factor VIII at 1.5 Å resolution

Author

Listed:
  • Kathleen P. Pratt

    (Program in Structural Biology, Fred Hutchinson Cancer Research Center
    University of Washington, Box 357350)

  • Betty W. Shen

    (Program in Structural Biology, Fred Hutchinson Cancer Research Center)

  • Kazuya Takeshima

    (University of Washington, Box 357350)

  • Earl W. Davie

    (University of Washington, Box 357350)

  • Kazuo Fujikawa

    (University of Washington, Box 357350)

  • Barry L. Stoddard

    (Program in Structural Biology, Fred Hutchinson Cancer Research Center)

Abstract

Human factor VIII is a plasma glycoprotein that has a critical role in blood coagulation1,2. Factor VIII circulates as a complex with von Willebrand factor3. After cleavage by thrombin, factor VIIIa associates with factor IXa at the surface of activated platelets or endothelial cells4,5. This complex activates factor X (refs 6, 7), which in turn converts prothrombin to thrombin in the presence of factor Va (refs 8, 9). The carboxyl-terminal C2 domain of factor VIII contains sites that are essential for its binding to von Willebrand factor and to negatively charged phospholipid surfaces4,10,11. Here we report the structure of human factor VIII C2 domain at 1.5 Å resolution. The structure reveals a β-sandwich core, from which two β-turns and a loop display a group of solvent-exposed hydrophobic residues. Behind the hydrophobic surface lies a ring of positively charged residues. This motif suggests a mechanism for membrane binding involving both hydrophobic and electrostatic interactions. The structure explains, in part, mutations in the C2 region of factor VIII that lead to bleeding disorders in haemophilia A.

Suggested Citation

  • Kathleen P. Pratt & Betty W. Shen & Kazuya Takeshima & Earl W. Davie & Kazuo Fujikawa & Barry L. Stoddard, 1999. "Structure of the C2 domain of human factor VIII at 1.5 Å resolution," Nature, Nature, vol. 402(6760), pages 439-442, November.
    • Handle: RePEc:nat:nature:v:402:y:1999:i:6760:d:10.1038_46601
    DOI: 10.1038/46601
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