血管性血友病因子 (VWF) 是一种由共价连接的单体组成的多聚体蛋白质，这些单体具有相同的结构域结构。尽管参与炎症、血管生成和癌症转移等过程，但 VWF 最出名的是其在止血中的作用，它可以作为凝血因子 VIII (FVIII) 的伴侣蛋白，并在血栓形成过程中促进血小板的募集。为了发挥止血作用，VWF 需要结合多种配体，包括 FVIII、血小板受体糖蛋白 Ib-α、VWF 裂解蛋白酶 ADAMTS13、内皮下胶原蛋白和整合素 α-IIb/β-3。重要的是，每种配体的相互作用受到不同的调节。这些绑定事件是如何完成和协调的？构成 VWF 蛋白的结构域的基本结构存在于原核生物和真核生物的数百种其他蛋白中。然而，在 VWF 背景下，特别是与其配体复合物中这些结构域的三维结构的测定表明，排他性的、VWF 特异性的结构适应已纳入其结构域中。他们解释了 VWF 如何同步、及时地结合其配体。在当前的综述中，我们重点关注与 VWF 主要配体相互作用的结构域，并讨论阐明这些结构域的三维结构如何有助于我们理解 VWF 功能是如何控制的。我们进一步详细介绍了与冯·维勒布兰德病相关的这些结构域中的突变如何调节 VWF 及其配体之间的相互作用。版权所有 © 2024 美国血液学会。

Von Willebrand factor (VWF) is a multimeric protein consisting of covalently linked monomers, which share an identical domain architecture. Although involved in processes like inflammation, angiogenesis and cancer metastasis, VWF is mostly known for its role in hemostasis, by acting as a chaperone-protein for coagulation factor VIII (FVIII) and by contributing to the recruitment of platelets during thrombus formation. To serve its role in hemostasis, VWF needs to bind a variety of ligands, including FVIII, platelet-receptor glycoprotein Ib-alpha, VWF-cleaving protease ADAMTS13, sub-endothelial collagen and integrin alpha-IIb/beta-3. Importantly, interactions are differently regulated for each of these ligands. How are these binding events accomplished and coordinated? The basic structures of the domains that constitute the VWF protein are found in hundreds of other proteins of pro- and eukaryotic organisms. However, the determination of the three-dimensional structures of these domains within the VWF context and especially in complex with its ligands reveals that exclusive, VWF-specific structural adaptations have been incorporated in its domains. They provide an explanation of how VWF binds its ligands in a synchronized and timely fashion. In the current review, we have focused on the domains that interact with the main ligands of VWF and discuss how elucidating the three-dimensional structures of these domains has contributed to our understanding of how VWF function is controlled. We further detail how mutations in these domains that are associated with von Willebrand disease modulate the interaction between VWF and its ligands.Copyright © 2024 American Society of Hematology.