Abstract
Heat shock protein 90 (Hsp90) is a dimeric molecular chaperone that undergoes large conformational changes during its functional cycle. It has been established that conformational switch points exist in the N-terminal (Hsp90-N) and C-terminal (Hsp90-C) domains of Hsp90, however information for switch points in the large middle-domain (Hsp90-M) is scarce. Here we report on a tryptophan residue in Hsp90-M as a new type of switch point. Our study shows that this conserved tryptophan senses the interaction of Hsp90 with a stringent client protein and transfers this information via a cation–π interaction with a neighboring lysine. Mutations at this position hamper the communication between domains and the ability of a client protein to affect the Hsp90 cycle. The residue thus allows Hsp90 to transmit information on the binding of a client from Hsp90-M to Hsp90-N which is important for progression of the conformational cycle and the efficient processing of client proteins.
Highlights
Heat shock protein 90 (Hsp90) is a dimeric molecular chaperone that undergoes large conformational changes during its functional cycle
Some elements contributing to this process are known, such as the rearrangements in the Nterminal domains in response to ATP binding which eventually lead to their dimerization via β-strand swapping[14,15,43] or residues in Hsp[90] occurs via its C-terminal domains (Hsp90-C) responding to post-translational modifications[24]
We find that this residue functions as a switch point in Hsp90-N and middle domains (Hsp90-M), important for specific conformational changes associated with client processing
Summary
Heat shock protein 90 (Hsp90) is a dimeric molecular chaperone that undergoes large conformational changes during its functional cycle. Molecular dynamics (MD) simulations of Hsp[90] combined with biochemical experiments identified further allosteric effects of specific residues[26] Together, these data show that local changes in sidechain character can have long-range effects on sites distant in the protein. We identified and characterized an important switch point, a conserved tryptophan (W300 in yeast Hsp90) which is localized in Hsp90-M adjacent to the GR client binding site[27]. It has been shown that mutation of this tryptophan to alanine (W300A) impairs yeast growth at 30 °C, affects client processing and co-chaperone binding[31,32,33,34,35] These results suggest that W300 plays a direct role concerning interactions with the M-domain of Hsp[90]. Our results demonstrate that W300 is a molecular switch point which responds to client interaction and induces long-range conformational changes in Hsp[90] required for client activation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
