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.
A better understanding of the Hsp90 chaperone system has important implications for both basic cell functions and medicinal approaches, as demonstrated by the large number of progressing clinical trials. Given the broad spectrum and sheer number of Hsp90 protein clients, it would be useful to develop more directed means of disrupting the Hsp90 chaperone system and cochaperones are one promising avenue to more selectively interfere with the Hsp90 network. Our proposed work will provide insights into the functional capacity of the Sba1 cochaperone network that likely helps achieve cellular proteostasis and will serve as a resource for developing more selective therapeutic reagents to dissect the Hsp90 chaperone system.
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|Echtenkamp, Frank J; Zelin, Elena; Oxelmark, Ellinor et al. (2011) Global functional map of the p23 molecular chaperone reveals an extensive cellular network. Mol Cell 43:229-41|