Structural bases of ADAMTS-13 and VWF A2 interactions

ADAMTS-13 和 VWF A2 相互作用的结构基础

基本信息

批准号：
8209109
负责人：
Cheng Zhu
金额：
$ 5.56万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8209109
关键词：
ADAMTS Academy Adhesions Adhesiveness Binding Binding Sites Biomechanics Biophysics Blood Circulation Blood Platelets Blood Vessels Blood flow Cells China Chinese People Cleaved cell Collaborations Complement Data Defect Disease Dissociation Environment Goals Grant Hemostatic Agents Hemostatic function Individual Injury Institutes Kinetics Lead Measures Mechanics Metalloproteases Modeling Molecular Molecular Conformation Molecular Models Mutagenesis Mutation Parents Pathology Pathway interactions Physiological Physiology Poly A Principal Investigator Process Property Proteolysis Regulation Research Science Site Structure Testing Thrombosis Thrombotic Thrombocytopenic Purpura Triad Acrylic Resin United States National Institutes of Health Variant base computer studies design insight model development models and simulation molecular dynamics molecular modeling mutant novel therapeutic intervention parent grant professor programs research study simulation single molecule von Willebrand Disease von Willebrand Factor

项目摘要

PROJECT SUMMARY This research will be done primarily at Institute of Biophysics, Chinese Academy of Sciences in Beijing, China in collaboration with Professor Jizhong Lou as an extension of NIH grant R01 HL093723- 01A1. This FIRCA application has a due objective: 1) to expand and enhance the parent grant and 2) to increase the research capacity of Dr. Jizhong Lou's group. The goal of this and the parent proposal is to elucidate the mechanical regulation of molecular interactions between von Willebrand factor and ADAMTS- 13, which are key interactions on physiological hemostasis and pathological thrombosis. Malfunction in the interactions may lead to von Willebrand disease and thrombotic thrombocytopenic purpura. ADAMTS- 13/VWF interaction are regulated mechanically as they take place in the hydrodynamic environment of the circulation. Our hypothesis for this FIRCA grant is that hydrodynamic forces induce the unfolding of VWF A2 domain which promote its interactions to ADAMTS-13, the binding with ADAMTS-13 will also lead to the conformational changes on ADAMTS-13 for efficient proteolysis and the conformations are regulated by the degree of A2 unfolding and mechanical forces. The broad hypothesis will be tested in two specific aims: 1) Elucidate the structural mechanisms of type 2A VWD by comparing the force- and thermo-induced unfolding pathways of wild-type (WT) VWF A2 domain and a panel of mutant VWF A2 domains, and 2) 2.Develop atomic models for the ADAMTS-13/A2 interactions and determine how these interactions regulate A2 unfolding and ADAMTS-13 conformational changes. These specific aims are computational studies, which complement the parent grant. The molecular dynamics simulations and molecular modeling proposed in the FIRCA grant will help to interpret the experimental data obtained from the parent grant and provide opportunities to design new experiments to test the overall hypothesis of the parent and the FIRCA grant. Decoding how mechanical forces regulate VWF A2 unfolding, ADAMTS-13 conformations and the interactions between the two molecules will provide key insights into vascular physiology and pathology. As a result, the data may office new therapeutic approaches to relevant diseases.

项目概要该研究主要在中国科学院生物物理研究所完成中国北京与楼继忠教授合作，作为 NIH 拨款 R01 HL093723- 的延伸 01A1。该 FIRCA 申请有一个应有的目标：1) 扩大和增强母公司补助金，2) 提高楼继忠博士课题组的研究能力。本提案和父提案的目标是阐明冯维勒布兰德因子和 ADAMTS 之间分子相互作用的机械调节 13，这是生理性止血和病理性血栓形成的关键相互作用。故障发生在相互作用可能导致血管性血友病和血栓性血小板减少性紫癜。 ADAMTS- 13/VWF 相互作用受到机械调节，因为它们发生在流体动力环境中循环。我们对这项 FIRCA 资助的假设是水动力诱导 VWF A2 的展开域促进其与 ADAMTS-13 的相互作用，与 ADAMTS-13 的结合也会导致 ADAMTS-13 上的构象变化可实现有效的蛋白水解，并且构象受 A2 展开程度和机械力。广泛的假设将在两个具体目标上进行检验：1) 通过比较力诱导和热诱导的展开来阐明 2A 型 VWD 的结构机制野生型 (WT) VWF A2 结构域和一组突变型 VWF A2 结构域的通路，以及 2) 2. 开发 ADAMTS-13/A2 相互作用的原子模型并确定这些相互作用如何调节 A2 展开和 ADAMTS-13 构象变化。这些具体目标是计算研究，补充家长补助金。提出的分子动力学模拟和分子建模 FIRCA 资助将有助于解释从父资助获得的实验数据并提供设计新实验来检验父母和 FIRCA 资助的总体假设的机会。解码机械力如何调节 VWF A2 展开、ADAMTS-13 构象和两种分子之间的相互作用将为血管生理学和病理学提供重要的见解。作为因此，这些数据可能会为相关疾病提供新的治疗方法。