Dissecting Structure-Encoded Determinants of Allosteric Cross-Talk between Post-Translational Modification Sites in the Hsp90 Chaperones

Stetz, Gabrielle; Tse, Amanda; Verkhivker, Gennady M.

doi:10.1038/s41598-018-25329-4

Cited by 47 publications

(52 citation statements)

References 106 publications

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“…In agreement with these ideas, recent computational analysis showed potential allosteric coupling between residue S485 and the NTD region that could be critical for interdomain communication (Stetz et al 2018). Our findings emphasize the importance of the SdC region in Hsp90 cycle regulation in vivo and suggest S485 and other SdC residues are involved in such signaling that results in promoting NTD dimerization.…”

Section: Discussionsupporting

confidence: 88%

Dual Roles for Yeast Sti1/Hop in Regulating the Hsp90 Chaperone Cycle

et al. 2018

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The Hsp90 chaperone is regulated by many cochaperones that tune its activities, but how they act to coordinate various steps in the reaction cycle is unclear. The primary role of Hsp70/Hsp90 cochaperone Sti1 (Hop in mammals) is to bridge Hsp70 and Hsp90 to facilitate client transfer. Sti1 is not essential, so Hsp90 can interact with Hsp70 without Sti1. Nevertheless, many Hsp90 mutations make Sti1 necessary. We noted that Sti1-dependent mutations cluster in regions proximal to N-terminal domains (SdN) or C-terminal domains (SdC), which are known to be important for interaction with Hsp70 or clients, respectively. To uncover mechanistic details of Sti1-Hsp90 cooperation, we identified intramolecular suppressors of the Hsp90 mutants and assessed their physical, functional, and genetic interactions with Hsp70, Sti1, and other cochaperones. Our findings suggest Hsp90 SdN and SdC mutants depend on the same interaction with Sti1, but for different reasons. Sti1 promoted an essential Hsp70 interaction in the SdN region and supported SdC-region function by establishing an Hsp90 conformation crucial for capturing clients and progressing through the reaction cycle. We find the Hsp70 interaction and relationship with Sti1/Hop is conserved in the human Hsp90 system. Our work consolidates and clarifies much structural, biochemical, and computational data to define roles of Sti1/Hop in coordinating Hsp70 binding and client transfer with progression of the Hsp90 reaction cycle.

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Section: Discussionsupporting

confidence: 88%

Dual Roles for Yeast Sti1/Hop in Regulating the Hsp90 Chaperone Cycle

et al. 2018

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“…Nevertheless, all of them influence the molecular properties that determine the 3D conformation, the conformational dynamics, and thereby also the function of a protein ( Schwenkert et al, 2014 ; Lewandowski et al, 2015 ; Schummel et al, 2016 ; Wei et al, 2016 ; Csizmok and Forman-Kay, 2018 ). The chaperone protein Hsp90 ( Schopf et al, 2017 ) is an excellent test system to investigate diverse regulation mechanisms ( Stetz et al, 2018 ). It was recently discussed that a single PTM can functionally mimic a specific co-chaperone interaction in human Hsp90 ( Zuehlke et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Controlling protein function by fine-tuning conformational flexibility

Schmid

Hugel

2020

eLife

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In a living cell, protein function is regulated in several ways, including post-translational modifications (PTMs), protein-protein interaction, or by the global environment (e.g. crowding or phase separation). While site-specific PTMs act very locally on the protein, specific protein interactions typically affect larger (sub-)domains, and global changes affect the whole protein non-specifically. Herein, we directly observe protein regulation under three different degrees of localization, and present the effects on the Hsp90 chaperone system at the levels of conformational steady states, kinetics and protein function. Interestingly using single-molecule FRET, we find that similar functional and conformational steady states are caused by completely different underlying kinetics. We disentangle specific and non-specific effects that control Hsp90’s ATPase function, which has remained a puzzle up to now. Lastly, we introduce a new mechanistic concept: functional stimulation through conformational confinement. Our results demonstrate how cellular protein regulation works by fine-tuning the conformational state space of proteins.

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“…Together with the appearance of cochaperones, an increasing variety and abundance of PTMs allows for precise tuning of the Hsp90 chaperone cycle in response to both diverse environmental cues and the needs of specific clients. Further, molecular modeling studies suggest that some Hsp90 PTMs serve as conformational switches that facilitate allosteric regulation of chaperone structure during the chaperone cycle 14 .…”

Section: Introductionmentioning

confidence: 99%

Hsp90 middle domain phosphorylation initiates a complex conformational program to recruit the ATPase-stimulating cochaperone Aha1

Beebe

Chavez

et al. 2019

Nat Commun

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Complex conformational dynamics are essential for function of the dimeric molecular chaperone heat shock protein 90 (Hsp90), including transient, ATP-biased N-domain dimerization that is necessary to attain ATPase competence. The intrinsic, but weak, ATP hydrolyzing activity of human Hsp90 is markedly enhanced by the co-chaperone Aha1. However, the cellular concentration of Aha1 is substoichiometric relative to Hsp90. Here we report that initial recruitment of this cochaperone to Hsp90 is markedly enhanced by phosphorylation of a highly conserved tyrosine (Y313 in Hsp90α) in the Hsp90 middle domain. Importantly, phosphomimetic mutation of Y313 promotes formation of a transient complex in which both N- and C-domains of Aha1 bind to distinct surfaces of the middle domains of opposing Hsp90 protomers prior to ATP-directed N-domain dimerization. Thus, Y313 represents a phosphorylation-sensitive conformational switch, engaged early after client loading, that affects both local and long-range conformational dynamics to facilitate initial recruitment of Aha1 to Hsp90.

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Dissecting Structure-Encoded Determinants of Allosteric Cross-Talk between Post-Translational Modification Sites in the Hsp90 Chaperones

Cited by 47 publications

References 106 publications

Dual Roles for Yeast Sti1/Hop in Regulating the Hsp90 Chaperone Cycle

Dual Roles for Yeast Sti1/Hop in Regulating the Hsp90 Chaperone Cycle

Controlling protein function by fine-tuning conformational flexibility

Hsp90 middle domain phosphorylation initiates a complex conformational program to recruit the ATPase-stimulating cochaperone Aha1

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