Crystal structure of the von Willebrand factor A1 domain and implications for the binding of platelet glycoprotein Ib
Crystal structure of the von Willebrand factor A1 domain and implications for the binding of platelet glycoprotein Ib
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DOI：
10.1074/jbc.273.17.10396
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发表时间：
1998-04-24
影响因子：
4.8
通讯作者：
Liddington, R
中科院分区：
文献类型：
--
作者：
Emsley, J;Cruz, M;Liddington, R
血管性血友病因子（vWF）是一种多聚体蛋白，其在高流量/剪切条件下介导血小板粘附到血管损伤部位的暴露的内皮下。vWF的Al结构域（vWF-A1）形成血小板糖蛋白Ib（GpIb）的主要结合位点，这是一种受到严格调控的相互作用。我们在这里报告的晶体结构的vWF-A1域在2.3埃分辨率。如所预期的，总体折叠与vWF-A3和整联蛋白I结构域的折叠相似。然而，该结构还包含N-和C-末端臂，其缠绕在结构域的下表面上。与整合素I结构域不同，vWF-A1不含金属离子依赖性粘附位点基序。对现有诱变数据的分析表明，激活剂肉毒素结合到含有螺旋α 5和α 6的结构域的右侧面。GpIb的可能结合位点是结构域的前表面和上表面。导致组成性GpIb结合（血管性血友病IIb型）的天然突变聚集在不同的位点，在下表面和末端臂之间的界面处，表明它们破坏了调节区，而不是形成主要GpIb结合位点的一部分。一个可能的途径传播的结构变化从监管区的配体结合表面进行了讨论。
von Willebrand Factor (vWF) is a multimeric protein that mediates platelet adhesion to exposed subendothelium at sites of vascular injury under conditions of high flow/shear. The Al domain of vWF (vWF-A1) forms the principal binding site for platelet glycoprotein Ib (GpIb), an interaction that is tightly regulated. We report here the crystal structure of the vWF-A1 domain at 2.3-Angstrom resolution. As expected, the overall fold is similar to that of the vWF-A3 and integrin I domains. However, the structure also contains N- and C-terminal arms that wrap across the lower surface of the domain. Unlike the integrin I domains, vWF-A1 does not contain a metal ion-dependent adhesion site motif. Analysis of the available mutagenesis data suggests that the activator botrocetin binds to the right-hand face of the domain containing helices alpha 5 and alpha 6. Possible binding sites for GpIb are the front and upper surfaces of the domain. Natural mutations that lead to constitutive GpIb binding (von Willebrand type IIb disease) cluster in a different site, at the interface between the lower surface and the terminal arms, suggesting that they disrupt a regulatory region rather than forming part of the primary GpIb binding site. A possible pathway for propagating structural changes from the regulatory region to the ligand-binding surface is discussed.