Structural basis of von Willebrand factor activation by the snake toxin botrocetin
Structural basis of von Willebrand factor activation by the snake toxin botrocetin
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DOI：
10.1016/s0969-2126(02)00787-6
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发表时间：
2002-07-01
期刊：
影响因子：
5.7
通讯作者：
Liddington, RC
中科院分区：
文献类型：
--
作者：
Fukuda, K;Doggett, TA;Liddington, RC
血管性血友病因子 (vWF) 的 A1 结构域通过与血小板受体糖蛋白 1b (GpIb) 结合（一种受流体动力剪切力调节的相互作用）来介导血小板粘附到血管损伤部位。 A1 的 GpIb 结合表面与调节区不同，表明配体结合是变构控制的。在这里，我们报告了“功能获得”突变体 A1 结构域 (I546V) 及其与外源激活剂 botrocetin 的复合物的晶体结构。我们发现 botrocetin 将突变体 A1 转变回野生型构象，这表明亲和力是通过增加 GpIb 结合表面而不是通过变构控制来增强的。血流下血小板粘附的功能研究进一步表明，激活机制与功能获得突变的机制不同。
The A1 domain of von Willebrand factor (vWF) mediates platelet adhesion to sites of vascular injury by binding to the platelet receptor glycoprotein 1b (GpIb), an interaction that is regulated by hydrodynamic shear forces. The GpIb binding surface of A1 is distinct from a regulatory region, suggesting that ligand binding is controlled allosterically. Here we report the crystal structures of the "gain-of-function" mutant A1 domain (I546V) and its complex with the exogenous activator botrocetin. We show that botrocetin switches the mutant Al back toward the wild-type conformation, suggesting that affinity is enhanced by augmenting the GpIb binding surface rather than through allosteric control. Functional studies of platelet adhesion under flow further suggest that the activation mechanism is distinct from that of the gain-of-function mutation.