How unique structural adaptations support and coordinate the complex function of von Willebrand factor.

IF 21 1区 医学 Q1 HEMATOLOGY Blood Pub Date : 2024-11-21 DOI:10.1182/blood.2023023277
Peter J Lenting, Cécile V Denis, Olivier D Christophe
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Abstract

Abstract: von Willebrand factor (VWF) is a multimeric protein consisting of covalently linked monomers, which share an identical domain architecture. Although involved in processes such as 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-α, VWF-cleaving protease ADAMTS13, subendothelial collagen, and integrin α-IIb/β-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 prokaryotic and eukaryotic organisms. However, the determination of the 3-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 this review, we have focused on the domains that interact with the main ligands of VWF and discuss how elucidating the 3-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.

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冯-维勒布兰德因子:独特的结构适应如何支持和协调其复杂功能。
冯-威廉因子(VWF)是一种多聚蛋白,由共价连接的单体组成,这些单体具有相同的结构域。虽然 VWF 参与了炎症、血管生成和癌症转移等过程,但它在止血方面的作用最为人熟知,因为它是凝血因子 VIII(FVIII)的伴侣蛋白,并在血栓形成过程中有助于血小板的募集。为了在止血过程中发挥作用,VWF 需要与多种配体结合,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 alpha-IIb/beta-3。重要的是,这些配体之间的相互作用调节方式各不相同。这些结合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质中。然而,通过测定这些结构域在 VWF 内的三维结构,特别是与配体的复合结构,我们发现这些结构域中包含了 VWF 特有的独特结构调整。它们为 VWF 如何以同步和及时的方式结合配体提供了解释。在本综述中,我们重点研究了与 VWF 主要配体相互作用的结构域,并讨论了阐明这些结构域的三维结构如何有助于我们理解 VWF 功能是如何受控的。我们还进一步详细介绍了与冯-威廉氏病相关的这些结构域的突变是如何调节 VWF 与其配体之间的相互作用的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Blood
Blood 医学-血液学
CiteScore
23.60
自引率
3.90%
发文量
955
审稿时长
1 months
期刊介绍: Blood, the official journal of the American Society of Hematology, published online and in print, provides an international forum for the publication of original articles describing basic laboratory, translational, and clinical investigations in hematology. Primary research articles will be published under the following scientific categories: Clinical Trials and Observations; Gene Therapy; Hematopoiesis and Stem Cells; Immunobiology and Immunotherapy scope; Myeloid Neoplasia; Lymphoid Neoplasia; Phagocytes, Granulocytes and Myelopoiesis; Platelets and Thrombopoiesis; Red Cells, Iron and Erythropoiesis; Thrombosis and Hemostasis; Transfusion Medicine; Transplantation; and Vascular Biology. Papers can be listed under more than one category as appropriate.
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