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SHR Neuro Cancer Cardio Lipid Metab Microb

Zierer, BK; Rübbelke, M; Tippel, F; Madl, T; Schopf, FH; Rutz, DA; Richter, K; Sattler, M; Buchner, J.
Importance of cycle timing for the function of the molecular chaperone Hsp90.
Nat Struct Mol Biol. 2016; 23(11):1020-1028 Doi: 10.1038/nsmb.3305 [OPEN ACCESS]
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Co-authors Med Uni Graz: Madl Tobias
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Abstract:: Hsp90 couples ATP hydrolysis to large conformational changes essential for activation of client proteins. The structural transitions involve dimerization of the N-terminal domains and formation of 'closed states' involving the N-terminal and middle domains. Here, we used Hsp90 mutants that modulate ATPase activity and biological function as probes to address the importance of conformational cycling for Hsp90 activity. We found no correlation between the speed of ATP turnover and the in vivo activity of Hsp90: some mutants with almost normal ATPase activity were lethal, and some mutants with lower or undetectable ATPase activity were viable. Our analysis showed that it is crucial for Hsp90 to attain and spend time in certain conformational states: a certain dwell time in open states is required for optimal processing of client proteins, whereas a prolonged population of closed states has negative effects. Thus, the timing of conformational transitions is crucial for Hsp90 function and not cycle speed.
Find related publications in this database (using NLM MeSH Indexing): Adenosine Triphosphatases - chemistry; Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Adenosine Triphosphate - metabolism; HSP90 Heat-Shock Proteins - chemistry; HSP90 Heat-Shock Proteins - genetics; HSP90 Heat-Shock Proteins - metabolism; Models, Molecular -; Point Mutation -; Protein Conformation -; Protein Domains -; Saccharomyces cerevisiae - chemistry; Saccharomyces cerevisiae - cytology; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - chemistry; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism