Hsp90 is a drug target for anticancer therapies and is also involved in other human diseases such as tauopathies 1, 2, 3, 4. It regulates a wide range of client proteins. Hsp90 is an abundant, highly conserved molecular chaperone that is essential in eukaryotes. ATP hydrolysis is not necessary for this exchange but provides an important control point in the cycle responsive to regulation by co-chaperones. Our findings support earlier suggestions that exchange of ATP for ADP is critical for Hsp90 function. Thus, the requirement of ATP for Hsp90 to maintain viability of evolutionarily distant eukaryotic organisms does not appear to depend on energy from ATP hydrolysis. We identify second-site suppressors of EA that rescue its conditional defects and allow EA versions of all Hsp90 orthologs tested to support nearly normal growth of both organisms, without restoring ATP hydrolysis. Hsp90 orthologs with the analogous EA mutation from several eukaryotic species, including humans and disease organisms, support viability of both S. We find binding of ATP to Hsp82-E33A induces the conformational dynamics needed for Hsp90 function. cerevisiae, although it displays conditional phenotypes. Here we confirm earlier findings that the Hsp82-E33A mutant, which binds ATP but does not hydrolyze it, supports viability of S. Current models of Hsp90 function, which include many conformational rearrangements, specify a requirement of ATP hydrolysis. Hsp90 is an essential eukaryotic chaperone that regulates the activity of many client proteins.
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