Structural bases of ADAMTS-13 and VWF A2 interactions

ADAMTS-13 和 VWF A2 相互作用的结构基础

• 批准号: 8019207
• 负责人: Cheng Zhu
• 金额: $ 6.73万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 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/8019207
• 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

DESCRIPTION (provided by applicant): 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 is 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 promotes 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. PUBLIC HEALTH RELEVANCE: This FIRCA proposal extends the parent grant in several ways. Information obtained from the parent and this FIRCA grants will help develop new therapeutic approaches to type 2A von Willebrand disease and thrombotic thrombocytopenic purpura.

描述（由申请人提供）：这项研究将主要在中国北京的中国科学院生物物理研究所与楼继忠教授合作完成，作为 NIH 拨款 R01 HL093723-01A1 的延伸。该 FIRCA 申请有一个应有的目标：1) 扩大和加强家长资助，2) 提高楼继忠博士团队的研究能力。本提案和母提案的目标是阐明冯·维勒布兰德因子和 ADAMTS-13 之间分子相互作用的机械调节，这是生理性止血和病理性血栓形成的关键相互作用。相互作用的故障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，因为它们发生在循环的水动力环境中。我们对这项 FIRCA 资助的假设是，水动力诱导 VWF A2 结构域的展开，从而促进其与 ADAMTS-13 的相互作用，与 ADAMTS-13 的结合也会导致 ADAMTS-13 的构象变化，以实现有效的蛋白水解，并且构象受到 A2 展开程度和机械力的调节。广泛的假设将在两个具体目标上进行测试：1) 通过比较野生型 (WT) VWF A2 结构域和一组突变 VWF A2 结构域的力和热诱导的展开途径来阐明 2A 型 VWD 的结构机制，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，是对家长资助的补充。 FIRCA 资助中提出的分子动力学模拟和分子建模将有助于解释从母体资助中获得的实验数据，并提供设计新实验的机会，以检验母体和 FIRCA 资助的总体假设。解读机械力如何调节 VWF A2 展开、ADAMTS-13 构象以及两个分子之间的相互作用将为血管生理学和病理学提供重要见解。因此，这些数据可能会为相关疾病提供新的治疗方法。 公共卫生相关性：该 FIRCA 提案以多种方式扩展了家长补助金。从家长处获得的信息以及 FIRCA 拨款将有助于开发 2A 型冯维勒布兰德病和血栓性血小板减少性紫癜的新治疗方法。