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DOI: 10.1055/s-0037-1613761
Structural Basis for Hemophilia A Caused by Mutations in the C Domains of Blood Coagulation Factor VIII
Publication History
Received
12 July 1999
Accepted after revision
17 September 1999
Publication Date:
06 December 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200001/lookinside/thumbnails/10-1055-s-0037-1613761-1.jpg)
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.
* This is Manuscript number 12360-MEM from The Scripps Research Institute
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