The Hsp90 molecular chaperone system

描述（由申请人提供）：我们的长期目标是了解Hsp90分子伴侣系统的细胞广度和影响。为了剖析这个庞大而多样的伴侣网络，我们利用高通量方法鉴定酵母p23伴侣Sba1的遗传和物理相互作用物，它服务于酵母Hsp90 （Hsp82）伴侣系统的一个分支。出乎意料的是，生物信息学分析表明，Sba1子网既与已识别的Hsp82网络重叠，又拥有主权。值得注意的是，Sba1在DNA上或DNA附近发挥了很大的作用。因此，Sba1似乎将Hsp82系统的作用扩展到各种核事件，包括转录、染色质、端粒和DNA修复途径。我们将专注于端粒和DNA修复路径，以更好地了解Hsp90系统的组成部分如何影响核事件。为了研究Sba1伴侣的影响，我们将采用三管齐下的策略：a)利用体内试验来确定Sba1对dna相关活动的生理影响；B)遗传表型将用于鉴定功能性sba1等位基因；C)伴侣蛋白调控的分子机制将通过体外实验来描述。我们的研究将有助于理解Hsp90伴侣网络如何维持细胞蛋白质稳态，以及如何通过靶向伴侣来剖析这种广泛的伴侣系统，以开发针对Hsp90机制的更具选择性的治疗策略。

DESCRIPTION (provided by applicant): Our long-term objective is to understand the cellular breadth and impact of the Hsp90 molecular chaperone system. To dissect this large and diverse chaperone network we have exploited high-throughput approaches to identify genetic and physical interactors of the yeast p23 cochaperone Sba1, which serves one branch of the yeast Hsp90 (Hsp82) chaperone system. Unexpectedly, bioinformatic analysis indicates that the Sba1 subnet both overlaps with and is sovereign to the identified Hsp82 network. Notably, a significant share of the Sba1 hits function at or near DNA. Thus, Sba1 appears to extend the role of the Hsp82 system to a variety of nuclear events including transcription, chromatin, telomere and DNA repair pathways. We will focus on telomere and DNA repair paths to better understand how component ts of the Hsp90 system affect nuclear events. To investigate the influence of the Sba1 chaperone we will follow a three-pronged strategy in which a) in vivo assays will be utilized to establish the physiological effect of Sba1 on DNA-related activities; b) genetic phenotypes will be employed to identify functional sba1 alleles; c) the molecular mechanisms of chaperone-regulation on client proteins will be delineated using in vitro assays. Our studies will contribute to the comprehension of how the Hsp90 chaperone network maintains cellular proteostasis and how this broad chaperone system might be dissected by targeting cochaperones to develop more selective therapeutic strategies that are directed at the Hsp90 machinery.