Reference: Richter K, et al. (2008) Conserved conformational changes in the ATPase cycle of human hsp90. J Biol Chem 283(26):17757-65

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Abstract


The dimeric molecular chaperone Hsp90 is required for the activation and stabilization of hundreds of substrate proteins, many of which participate in signal transduction pathways. The activation process depends on the hydrolysis of ATP by Hsp90. Hsp90 consists of a C-terminal dimerization domain, a middle domain, which may interact with substrate protein, and an N-terminal ATP-binding domain. A complex cycle of conformational changes has been proposed for the ATPase cycle of yeast Hsp90 where a critical step during the reaction requires the transient N-terminal dimerization of the two protomers. The ATPase cycle of human Hsp90 is less well understood and significant differences have been proposed regarding key mechanistic aspects. ATP-hydrolysis by human Hsp90 and Hsp90 is tenfold slower than that of yeast Hsp90. Despite these differences, our experiments suggest that the underlying enzymatic mechanisms are highly similar. In both cases, a concerted conformational rearrangement involving the N-terminal domains of both subunits is controlling the rate of ATP turnover and N-terminal crosstalk determines the rate-limiting steps. Furthermore, similar to yeast Hsp90, the slow ATP hydrolysis by human Hsp90s can be stimulated up to 70fold by the addition of the co-chaperone Aha1 from either man or yeast origin. Together, our results show that the basic principles of the Hsp90 ATPase reaction are conserved between yeast and man, including the dimerization of the N-terminal domains and its regulation by the repositioning of the ATP-lid from its original position to a catalytically competent one.

Reference Type
Journal Article
Authors
Richter K, Soroka J, Skalniak L, Leskovar A, Hessling M, Reinstein J, Buchner J
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