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: 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
• 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

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.

项目摘要 这项研究将主要在中国科学院生物物理学院进行 中国北京与Jizhong Lou教授合作，作为NIH Grant R01 HL093723-的扩展 01a1。此FIRCA应用程序具有适当的目标：1）扩展和增强父母的赠款，2） 提高Jizhong Lou小组的研究能力。这个目标和父母的建议是 阐明von Willebrand因子和Adamts-的分子相互作用的机械调节 13，这是关于生理止血和病理血栓形成的关键相互作用。故障 相互作用可能导致von Willebrand疾病和血小板性血小板减少性紫癜。 adamts- 13/vwf相互作用在机械上受到机械调节，因为它们发生在 循环。我们对这一FIRCA赠款的假设是流体动力诱导VWF A2的展开 促进其与ADAMTS-13相互作用的域，与ADAMTS-13的结合也将导致 ADAMTS-13的构象变化用于有效的蛋白水解和构象，由 A2展开和机械力的程度。广泛的假设将以两个具体的目的进行检验：1） 通过比较力和热诱导的展开，阐明了2A型VWD的结构机制 野生型（WT）VWF A2域和一个突变体VWF A2域的途径，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。这些具体目的是计算研究， 补充父母赠款。分子动力学模拟和分子建模 Firca Grant将有助于解释父母赠款获得的实验数据并提供 设计新实验的机会，以测试父母和FIRCA赠款的整体假设。 解码机械力如何调节VWF A2的展开，ADAMTS-13构象和 这两个分子之间的相互作用将为血管生理和病理学提供关键见解。作为 结果，数据可以为相关疾病的新治疗方法提供新的治疗方法。