Determinants of the Hsp90-client interaction

!项目摘要 Hsp 90是一种高度保守、丰富的分子伴侣，是一种全局性的细胞调节因子 在一个动态的ATP依赖性循环中与客户蛋白相互作用， 蛋白质折叠、运输和/或组装成多蛋白质复合物。热休克蛋白90- 依赖蛋白在许多形式的癌症和神经退行性疾病中具有关键作用。 疾病以及囊性纤维化和其他疾病。我们的长期目标是 了解Hsp 90和cochaperones如何在数百种蛋白质的折叠中合作， 具有不同序列和结构的蛋白质，足以形成小化合物 只影响Hsp 90客户端的子集。在第一个目标中，我们将使用一组新的 Hsp 90突变体，以了解如何结合封闭，ATP和 Hsp 90的客户结合构象微调客户折叠。技术创新 第二个目标是鉴定和表征影响不同亚群的Hsp 90突变体， 客户端蛋白质这些研究将有助于更好地理解 辅伴侣在调节顾客选择、构象和活动中的作用。 鉴定具有相似作用的Hsp 90突变体簇将为研究Hsp 90的分子机制铺平道路。 合理设计对体内Hsp 90受体具有选择性作用的化合物。 !

!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. !