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Thromb Haemost 2000; 83(01): 78-85
DOI: 10.1055/s-0037-1613761
Commentary
Schattauer GmbH

Structural Basis for Hemophilia A Caused by Mutations in the C Domains of Blood Coagulation Factor VIII

Andrew J. Gale
1   From the Departments of Molecular and Experimental Medicine and of Vascular Biology, The Scripps Research Institute, La Jolla, CA, USA
,
Jean-Luc Pellequer
2   Department of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA
,
Elizabeth D. Getzoff
2   Department of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA
,
John H. Griffin
1   From the Departments of Molecular and Experimental Medicine and of Vascular Biology, The Scripps Research Institute, La Jolla, CA, USA
› Author Affiliations
Further Information

Publication History

Received 12 July 1999

Accepted after revision 17 September 1999

Publication Date:
06 December 2017 (online)

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Summary

Three dimensional homology models for the C1 and C2 domains of factor VIII (FVIII) were generated. Each C domain formed a β-sandwich, and C1 was covalently connected to C2 in a head-to-head orientation. Of the >250 missense mutations that cause FVIII deficiency and hemophilia A, 34 are in the C domains. We used the FVIII C1-C2 model to infer the structural basis for the pathologic effects of these mutations. The mutated residues were divided into four categories: 15 conserved buried residues that affect normal packing of the hydrophobic side chains, 2 non-conserved buried residues that affect structure, 11 conserved exposed residues and 6 non-conserved exposed residues. The effects of all 34 missense mutations can be rationalized by predictable disruptions of FVIII structure while at most four mutations (S2069F, T2154I, R2209Q/G/L and E2181D) may affect residues directly involved in intermolecular interactions of FVIII/VIIIa with other coagulation factors or vWF.

Key words

Hemophilia A - Factor VIII - homology modeling - von Willebrand factor - coagulation

* This is Manuscript number 12360-MEM from The Scripps Research Institute


 

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