Gale A J, Pellequer J L, Getzoff E D, Griffin J H
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Thromb Haemost. 2000 Jan;83(1):78-85.
Three dimensional homology models for the C1 and C2 domains of factor VIII (FVIII) were generated. Each C domain formed a beta-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.
生成了凝血因子VIII（FVIII）C1和C2结构域的三维同源模型。每个C结构域形成一个β-折叠片层结构，且C1与C2以头对头的方向共价连接。在导致FVIII缺乏症和A型血友病的>250个错义突变中，有34个位于C结构域。我们使用FVIII C1-C2模型来推断这些突变病理效应的结构基础。突变残基分为四类：15个影响疏水侧链正常堆积的保守埋藏残基、2个影响结构的非保守埋藏残基、11个保守暴露残基和6个非保守暴露残基。所有34个错义突变的效应都可以通过FVIII结构的可预测破坏来解释，而最多有四个突变（S2069F、T2154I、R2209Q/G/L和E2181D）可能影响直接参与FVIII/VIIIa与其他凝血因子或血管性血友病因子（vWF）分子间相互作用的残基。
