Conformational Transitions of Heat Shock Proteins: The Case of Hsp90

Abstract

The most abundant cellular protein, Hsp90, partakes in many biological pathways, not only in times of induced stress, but also under normal physiological conditions. Its role in controlling proteostasis, by assisting in protein folding and reducing aggregation, together with its direct involvement in cancer cell survival and neurological disorders, makes this protein an attractive drug target. In solution, Hsp90 is a homodimer, with each subunit composed of three dynamically independent domains, contributing to the great structural flexibility and the ability to accommodate a large number of clients. Our molecular dynamic simulations of the E. coli homologue gave us a unique insight into observing the conformational transitions at atomic resolution. We observed dramatic structural rearrangements, independent of the initial state or the presence of nucleotides. The apo state was free to shift between the compact and fully stretched states, separated by a free energy barrier that was very close to the crystal open conformation. ATP binding stabilized the extended closed state, similar to the closed crystal state of HtpG. In the ADP-bound state the dynamics was limited to local motions in the N-terminal region, although the outward twisting of middle domains indicated the transitioning into an open state. Release of the nucleotides led to the formation of a compact conformation, guided by interactions between Asp287 and Asp292 from the middle domain and Lys103 from the N-terminal domain. The electrostatic interactions between opposite subunits appear to be key in directing the conformational change and making Hsp90 amenable to evolutionary fine-tuning that may regulate the populations of different conformations between homologues.