Determinants of the Hsp90-client interaction

！项目摘要 高度保守的丰富分子伴侣Hsp90是一种全球性的细胞调节因子 在一个动态的依赖于ATP的循环中与客户蛋白质相互作用以确保客户 蛋白质折叠、运输和/或组装成多蛋白质复合体。HSP90- 依赖蛋白在多种形式的癌症和神经退行性变中起关键作用 疾病以及囊性纤维化等疾病。我们的长期目标是 了解Hsp90和辅伴侣如何在数百个 具有足以形成小分子化合物的不同序列和结构的蛋白质 这只影响Hsp90客户的子集。在第一个目标中，我们将使用一组新颖的 HSP90突变体了解三个辅助伴侣如何结合闭合的、ATP和 Hsp90微调客户端折叠的客户端结合构象。技术创新 第二个目标是识别和表征影响不同亚群的Hsp90突变体 客户蛋白质。综合起来，这些研究将使我们能够更好地从机制上理解 辅伴蛋白在调节客户选择、构象和活性方面的作用。 鉴定具有相似效应的Hsp90突变体簇将为 合理设计对Hsp90客户具有体内选择性作用的化合物。 好了！

!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. !