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Abstract:
Heat−shock protein 90 (Hsp90) is an ATP−dependent molecular chaperone that associates dynamically with various co−chaperones during its chaperone cycle. Here we analyzed the role of the activating co−chaperone Aha1 in the progression of the yeast Hsp90 chaperone cycle and identified a critical ternary Hsp90 complex containing the co−chaperones Aha1 and Cpr6. Aha1 accelerates the intrinsically slow conformational transitions of Hsp90 to an N−terminally associated state but does not fully close the nucleotide−binding pocket yet. Cpr6 increases the affinity between Aha1 and Hsp90 and further stimulates the Hsp90 ATPase activity. Synergistically, Aha1 and Cpr6 displace the inhibitory co−chaperone Sti1 from Hsp90. To complete the cycle, Aha1 is released by the co−chaperone p23. Thus, at distinct steps during the Hsp90 chaperone cycle, co−chaperones selectively trap statistically distributed Hsp90 conformers and thus turn Hsp90 into a deterministic machine
