Hemophilic factor VIII C1- and C2-domain missense mutations and their modeling to the 1.5-angstrom human C2-domain crystal structure

M. L. Liu, B. W. Shen, S. Nakaya, K. P. Pratt, K. Fujikawa, E. W. Davie, B. L. Stoddard, A. R. Thompson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

Abstract

Factor VIII C domains contain key binding sites for von Willebrand factor (vWF) and phospholipid membranes. Hemophilic patients were screened for factor VIII C-domain mutations to provide a well-characterized series. Mutated residues ware localizad to the high-resolution C2 structure and to a homology model of C1. Of 30 families found with mutations in the C domains, there wera 14 missense changes, and 9 of these were novel. Of the missense mutations, 10 were associated with reduced vWF binding and 8 were at restdues with surface-exposed side chains. Six of the 10 mutants had nearly equivalent factor VIII clotting activity and antigen level, suggesting that reduced vWF binding could cause hemophilia by reducing factor VIII stability in circulation. When the present series was combined with previously described mutations from an online international database, 11 C1 and C2 mutations in patients with mild or moderately severe hemophilia A were associated with antibody-inhibitor development in at least one affected individual. Of these substitutions, 6 occurred at surface-exposed residues. As further details of the C1 structure and its interface with C2 become available, and as binding studies are performed on the plasma of more patients with hemophilic C-domain mutations, prediction of surface binding sites should improve, allowing confirmation by site-specific mutagenesis of surface exposed residues. (C) 2000 by The American Society of Hematology.

Original languageEnglish
Pages (from-to)979-987
Number of pages9
JournalBlood
Volume96
Issue number3
DOIs
StatePublished - 1 Aug 2000
Externally publishedYes

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