The molecular basis of VWF mechano-sensoring: Structure and interactions of VWF domains as the basis for regulation and aggregation

VWF 机械传感的分子基础：VWF 结构域的结构和相互作用作为调节和聚集的基础

• 批准号: 200681067
• 负责人: Professorin Dr. Frauke Gräter
• 金额: --
• 依托单位: Interdisziplinäres Zentrum für Wissenschaftliches Rechnen (IWR)
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/200681067?language=en
• 关键词: molecular; basis; VWF; mechano; sensoring

The function of von Willebrand factor, including adhesion and network formation, is tightly regulated by mechanical force, the molecular mechanism of which has remained elusive to a large extent. We recently have successfully put forward a new mechanism for the force-dependence of the VWF-platelet interaction. In this scenario, which is validated by experiments, VWF A1-GPIb binding is inhibited by a specific A1-A2 interaction, which is relieved by force due to shear flow. In the second funding period, we will extend our approach combining molecular modeling and Force-probe Molecular Dynamics simulations to the interaction of VWF A1 and A3 with collagen, for which we hypothesize a similar scenario. Secondly, as a major step towards a comprehensive understanding of the force-sensoring function of VWF, we aim at structural models and dynamic data under force of the C and D domains of VWF. We will attempt to explain on a molecular level the observed increased aggregation of VWF carrying polymorphism in the C4 domain. Finally, we will develop a coarse-grained Go-type polymer model, in which disulfide bonds can be reversibly broken and formed, in order to decipher mechanisms of force-dependent disulfide bond shuffling in D-domains, which carry protein disulfide isomerase motifs. Our work will contribute to the molecular-level understanding of how collective networks of wild-type and mutant VWF map to clinical presentation.

von Willebrand因子的功能，包括粘附和网络形成，受到机械力的严格调节，其分子机制在很大程度上仍然是难以捉摸的。最近，我们成功地提出了一种新的机制的力依赖性的VWF-血小板相互作用。在这种情况下，这是通过实验验证，VWF A1-GPIb结合被抑制的一个特定的A1-A2相互作用，这是缓解的力由于剪切流。在第二个资助期，我们将把我们的方法结合分子建模和力探针分子动力学模拟扩展到VWF A1和A3与胶原蛋白的相互作用，我们假设了类似的情况。其次，作为全面了解VWF力传感功能的重要一步，我们的目标是在VWF的C和D域的力下的结构模型和动态数据。我们将试图在分子水平上解释所观察到的C4结构域中携带多态性的VWF聚集增加。最后，我们将开发一个粗粒度的Go型聚合物模型，其中二硫键可以可逆地断裂和形成，以破译D-结构域中的力依赖性二硫键改组机制，其中携带蛋白质二硫键异构酶基序。我们的工作将有助于在分子水平上理解野生型和突变型VWF的集体网络如何映射到临床表现。