Crowding Activates Heat Shock Protein 90.

The Journal of Biological Chemistry
Jackson C HalpinTimothy O Street

Abstract

Hsp90 is a dimeric ATP-dependent chaperone involved in the folding, maturation, and activation of diverse target proteins. Extensive in vitro structural analysis has led to a working model of Hsp90's ATP-driven conformational cycle. An implicit assumption is that dilute experimental conditions do not significantly perturb Hsp90 structure and function. However, Hsp90 undergoes a dramatic open/closed conformational change, which raises the possibility that this assumption may not be valid for this chaperone. Indeed, here we show that the ATPase activity of Hsp90 is highly sensitive to molecular crowding, whereas the ATPase activities of Hsp60 and Hsp70 chaperones are insensitive to crowding conditions. Polymer crowders activate Hsp90 in a non-saturable manner, with increasing efficacy at increasing concentration. Crowders exhibit a non-linear relationship between their radius of gyration and the extent to which they activate Hsp90. This experimental relationship can be qualitatively recapitulated with simple structure-based volume calculations comparing open/closed configurations of Hsp90. Thermodynamic analysis indicates that crowding activation of Hsp90 is entropically driven, which is consistent with a model in which excluded ...Continue Reading

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Citations

Oct 25, 2016·Journal of Molecular Graphics & Modelling·Samir S Roy, Manju Kapoor
Sep 27, 2016·Protein Science : a Publication of the Protein Society·Shanshan Liu, Timothy O Street
Oct 4, 2017·Protein Science : a Publication of the Protein Society·Luis C AcostaAnnelise H Gorensek-Benitez
Jul 23, 2020·ELife·Sonja Schmid, Thorsten Hugel
Nov 18, 2019·Biophysics Reviews·Thiago V SeraphimWalid A Houry
Aug 22, 2017·Journal of Molecular Biology·Jackson C Halpin, Timothy O Street
Jun 17, 2019·Journal of Molecular Biology·Bin HuangTimothy O Street
Jun 6, 2017·ACS Nano·Michael W HudobaCarlos E Castro

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