EXAMINING THE ROLE OF THE ATPASE CYCLE OF HSP90 IN CONFORMATION AND COMPLEX FORM

检查 HSP90 的ATP酶循环在构象和复杂形式中的作用

• 批准号: 7954262
• 负责人: DAVID A. AGARD
• 金额: $ 0.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7954262
• 关键词: ATP Hydrolysis; ATP phosphohydrolase; Biochemical; Client; Complex; Computer Retrieval of Information on Scientific Projects Database; Coupled; Funding; Grant; Heat-Shock Proteins 90; Hydrolysis; Institution; Molecular Chaperones; Molecular Conformation; Phosphotransferases; Protein-Serine-Threonine Kinases; Proteins; Research; Research Personnel; Resources; Role; Signal Transduction; Source; TNFRSF5 gene; Techniques; United States National Institutes of Health; insight; structural biology; synchrotron radiation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The ubiquitous molecular chaperone Hsp90 is required in the maturation and maintanence of signalling and regulatory molecules including serine/threonine kinases. Hsp90 function requires ATP hydrolysis and this hydrolysis cycle is coupled to large conformational changes in the protein. Hsp90 is further regulated by the interaction of other proteins known as cochaperones. For the activation of kinase clients, Hsp90 forms a complex with the cochaperone p50. It is now well understood how the Hsp90 complex functions to activate its client proteins. Using SAXS, we propose to gain a structural insight into the mechanism of Hsp90's interaction with p50 and how this complex then interacts with the client protein Cdk4. We also propose to use SAXS to dissect the role of Hsp90's ATPase in regulating its interaction with both p50 and Cdk4. The structural information obtained from SAXS will be included with ongoing biochemical studies, and the combination of techniques will provide a detailed mechanistic insight into the activation of kinases by Hsp90.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 普遍存在的分子伴侣Hsp 90在包括丝氨酸/苏氨酸激酶的信号和调节分子的成熟和维持中是必需的。热休克蛋白90的功能需要ATP水解，这种水解循环与蛋白质中的大的构象变化相关联。热休克蛋白90还受到其他蛋白质（称为辅伴侣蛋白）相互作用的调节。为了激活激酶客户，Hsp 90与辅伴侣p50形成复合物。现在已经很好地理解了Hsp 90复合物是如何激活其客户蛋白的。使用SAXS，我们建议获得一个结构的洞察热休克蛋白90的与p50的相互作用的机制，以及如何这个复杂的客户端蛋白Cdk 4，然后相互作用。我们还建议使用SAXS剖析热休克蛋白90的ATP酶在调节其与p50和Cdk 4的相互作用的作用。从SAXS获得的结构信息将纳入正在进行的生化研究中，并且技术的结合将提供对Hsp 90激活激酶的详细机制见解。