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bioRxiv · 10.1101/2020.06.30.180695

Cryo-EM structures reveal a multistep mechanism of Hsp90 activation by co-chaperone Aha1

Liu, Y.·Sun, M.·Myasnikov, A. G.·Elnatan, D.·Delaeter, N.·Nguyenquang, M.·Agard, D.
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Abstract

Hsp90 is a ubiquitous molecular chaperone that facilitates the folding and maturation of hundreds of cellular “client” proteins. The ATP-driven client maturation process is regulated by a large number of co-chaperones. Among them, Aha1 is the most potent activator of Hsp90 ATPase activity and thus dramatically affects Hsp90’s client proteins. To understand the Aha1 activation mechanism, we determined full-length Hsp90:Aha1 structures in six different states by cryo-electron microscopy, including nucleotide-free semi-closed, nucleotide-bound pre-hydrolysis, and semi-hydrolyzed states. Our structures demonstrate that the two Aha1 domains can each interact with Hsp90 in two different modes, uncovering a complex multistep activation mechanism. The results show that Aha1 accelerates the chemical step of ATP hydrolysis like a conventional enzyme, but most unusually, catalyzes the rate-limiting large-scale conformational changes of Hsp90 fundamentally required for ATP hydrolysis. Our work provides a structural framework to guide small molecule development targeting this critical modulator of client protein maturation.Competing Interest StatementThe authors have declared no competing interest.View Full Text

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Liu, Y., Sun, M., Myasnikov, A. G., Elnatan, D., Delaeter, N., Nguyenquang, M., Agard, D.. 2020-07-01. Cryo-EM structures reveal a multistep mechanism of Hsp90 activation by co-chaperone Aha1. https://doi.org/10.1101/2020.06.30.180695

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