Crystal structure of human factor VIII: Implications for the formation of the factor IXa-factor VIIIa complex
Crystal structure of human factor VIII: Implications for the formation of the factor IXa-factor VIIIa complex
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DOI：
10.1016/j.str.2008.03.001
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发表时间：
2008-04-01
期刊：
影响因子：
5.7
通讯作者：
Furie, Bruce
中科院分区：
文献类型：
--
作者：
Ngo, Jacky Chi Ki;Huang, Mingdong;Furie, Bruce
因子 VIII 是一种前辅因子，在凝血中发挥关键作用，在血友病 A 中缺失或有缺陷。我们确定了 B 结构域缺失的人因子 VIII 的 X 射线晶体结构。该蛋白质由五个球状结构域组成，包含一个 Ca2+ 和两个 Cu2+ 离子。三个同源 A 结构域形成三角形异源三聚体，其中 A1 和 A3 结构域作为基础，分别与 C2 和 C1 结构域相互作用。结构同源的 C1 和 C2 结构域揭示了膜结合特征。基于生化研究，通过计算机对接构建了因子IXa-因子VIIIa复合物的模型。因子 IXa 包裹在因子 VIII 的侧面，并且延伸的界面跨越因子 VIII 重链和轻链。该模型提供了对因子 VIII 的激活以及因子 VIIIa 与因子 IXa 在膜表面上的相互作用的深入了解。
Factor VIII is a procofactor that plays a critical role in blood coagulation, and is missing or defective in hemophilia A. We determined the X-ray crystal structure of B domain-deleted human factor VIII. This protein is composed of five globular domains and contains one Ca2+ and two Cu2+ ions. The three homologous A domains form a triangular heterotrimer where the A1 and A3 domains serve as the base and interact with the C2 and C1 domains, respectively. The structurally homologous C1 and C2 domains reveal membrane binding features. Based on biochemical studies, a model of the factor IXa-factor VIIIa complex was constructed by in silico docking. Factor IXa wraps across the side of factor VIII, and an extended interface spans the factor VIII heavy and light chains. This model provides insight into the activation of factor VIII and the interaction of factor VIIIa with factor IXa on the membrane surface.