Determinants of the Hsp90-client interaction

Hsp90-客户端相互作用的决定因素

• 批准号: 10241422
• 负责人: JILL L JOHNSON
• 金额: $ 28.29万
• 依托单位: UNIVERSITY OF IDAHO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241422
• 关键词: ATP Hydrolysis; Affect; Binding; Binding Sites; Biochemical; Biological Assay; Biophysics; Cancerous; Cell physiology; Cells; Client; Complex; Cystic Fibrosis; Data; Defect; Development; Disease; Ensure; Exhibits; Genetic Transcription; Goals; Growth; Heat-Shock Proteins 90; Malignant Neoplasms; Mediating; Molecular Chaperones; Molecular Conformation; Molecular Disease; Multiprotein Complexes; Mutate; Mutation; Neurodegenerative Disorders; Nucleotides; Oncogenic; Outcome; Pathway interactions; Play; Proteins; Proteomics; Role; Signal Transduction; Specificity; Structure; Testing; Toxic effect; Yeasts; design; human disease; in vivo; inhibitor/antagonist; innovation; misfolded protein; mutant; novel; protein folding; tool; tumor progression; ubiquitin ligase

!Project Abstract The highly conserved abundant molecular chaperone Hsp90 is a global cellular regulator that interacts with client proteins in a dynamic ATP-dependent cycle to ensure client protein folding, transport and/or assembly into multiprotein complexes. Hsp90- dependent proteins have critical roles in many forms of cancer and neurodegenerative disease as well as cystic fibrosis and other diseases. Our long-term goal is to understand how Hsp90 and cochaperones cooperate in the folding of hundreds of proteins with diverse sequences and structures sufficiently to develop small compounds that only affect subsets of Hsp90 clients. In the first Aim, we will use a novel set of Hsp90 mutants to understand how three cochaperones that bind the closed, ATP and client-bound conformation of Hsp90 fine-tune client folding. The technically innovative second Aim will identify and characterize Hsp90 mutants that affect different subsets of client proteins. Together these studies will enable a better mechanistic understanding of the function of cochaperones in regulating client selection, conformation and activity. Identification of clusters of Hsp90 mutants with similar effects will pave a path towards rational design of compounds with selective effects on Hsp90 clients in vivo. !

！项目摘要 高度保守的丰富分子伴侣HSP90是一种全局细胞调节剂 在动态ATP依赖性周期中与客户端蛋白相互作用，以确保客户端 蛋白质折叠，传输和/或组装成多蛋白络合物。 HSP90- 依赖性蛋白质在多种形式的癌症和神经退行性中具有关键作用 疾病以及囊性纤维化和其他疾病。我们的长期目标是 了解HSP90和联合酮如何在数百个折叠中合作 具有多种序列和结构的蛋白质足够多，可以开发小型化合物 这仅影响HSP90客户端的子集。在第一个目标中，我们将使用一组新颖 HSP90突变体以了解如何结合封闭，ATP和 HSP90微调客户端折叠的客户结合构象。技术创新 第二个目标将识别并表征影响不同子集的HSP90突变体 客户蛋白。这些研究将共同​​使人们能够更好地理解 联合酮在调节客户选择，构象和活动中的功能。 识别具有相似效果的HSP90突变体的簇将铺平道路 对体内HSP90客户端具有选择性影响的化合物的合理设计。 呢