Allosteric Regulation Points Control the Conformational Dynamics of the Molecular Chaperone Hsp90

Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone
responsible for the activation, maturation, and trafficking of several
hundred client proteins in the cell. It is well known that (but not
understood how) residues far away from Hsp90's nucleotide binding pocket
can regulate its ATPase activity, a phenomenon called allosteric
regulation. Here, the computational design of allosteric mutations was
combined with in vitro and in vivo experiments to unravel
nucleotide-responsive hot spots in the regulation of Hsp90. With this
approach, we identified both activating and inhibiting regulation points
and show that changes in those amino acids affect the conformational
dynamics and ATPase activity of Hsp90 in vitro. Our observations that
activating mutations loosen and inhibiting mutations rigidify the
protein explain for the first time how Hsp90 changes in response to
allosteric mutations. Additionally, mutations of these allosteric
regulation points can be controlled by the interplay with Hsp90
co-chaperones, thus providing cells with an efficient mechanism of
modifying Hsp90's intrinsic properties via different layers of
regulation. Altogether, our results show that a framework for
transmitting conformational information exists in the Hsp90 structure.
(C) 2016 Elsevier Ltd. All rights reserved.