Intermolecular Interactions between Hsp90 and Hsp70

Doyle, Shannon M.; Hoskins, Joel R.; Kravats, Andrea N.; Heffner, Audrey L.; Garikapati, Srilakshmi; Wickner, Sue

doi:10.1016/j.jmb.2019.05.026

Cited by 40 publications

(27 citation statements)

References 73 publications

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“…This region on DnaK was confirmed to be important for the interaction with Hsp90

as substitution mutants in this region were defective in interaction with Hsp90

in vitro [ 66 ]. Chemical cross-linking experiments further showed the interaction of the NBD of DnaK and the middle domain of Hsp90

was direct and not the result of conformational changes elsewhere on the proteins, thus validating this computational model [ 70 ]. The bacterial chaperone systems have provided a useful tool in exploring the collaboration and direct interaction between the chaperones without additional complications from participation of other cochaperones throughout the chaperone cycle.…”

Section: Introductionmentioning

confidence: 78%

“…The bacterial chaperone systems have provided a useful tool in exploring the collaboration and direct interaction between the chaperones without additional complications from participation of other cochaperones throughout the chaperone cycle. There is also an abundance of structural information involving conformations in various nucleotide bound states [ 30 , 66 ], as well as functional information about the Hsp90-DnaK collaboration [ 12 , 15 , 64 , 66 , 67 , 70 , 71 , 72 ]. The direct interaction between Hsp70 and Hsp90 is conserved in yeast [ 67 ], suggesting potential similarities in mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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Structural Communication between the E. coli Chaperones DnaK and Hsp90

Grindle

Carter

Alao

et al. 2021

IJMS

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The 70 kDa and 90 kDa heat shock proteins Hsp70 and Hsp90 are two abundant and highly conserved ATP-dependent molecular chaperones that participate in the maintenance of cellular homeostasis. In Escherichia coli, Hsp90 (Hsp90Ec) and Hsp70 (DnaK) directly interact and collaborate in protein remodeling. Previous work has produced a model of the direct interaction of both chaperones. The locations of the residues involved have been confirmed and the model has been validated. In this study, we investigate the allosteric communication between Hsp90Ec and DnaK and how the chaperones couple their conformational cycles. Using elastic network models (ENM), normal mode analysis (NMA), and a structural perturbation method (SPM) of asymmetric and symmetric DnaK-Hsp90Ec, we extract biologically relevant vibrations and identify residues involved in allosteric signaling. When one DnaK is bound, the dominant normal modes favor biological motions that orient a substrate protein bound to DnaK within the substrate/client binding site of Hsp90Ec and release the substrate from the DnaK substrate binding domain. The presence of one DnaK molecule stabilizes the entire Hsp90Ec protomer to which it is bound. Conversely, the symmetric model of DnaK binding results in steric clashes of DnaK molecules and suggests that the Hsp90Ec and DnaK chaperone cycles operate independently. Together, this data supports an asymmetric binding of DnaK to Hsp90Ec.

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“…This region on DnaK was confirmed to be important for the interaction with Hsp90

as substitution mutants in this region were defective in interaction with Hsp90

in vitro [ 66 ]. Chemical cross-linking experiments further showed the interaction of the NBD of DnaK and the middle domain of Hsp90

Section: Introductionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Structural Communication between the E. coli Chaperones DnaK and Hsp90

Grindle

Carter

Alao

et al. 2021

IJMS

Self Cite

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“…Perhaps the best characterized interactions between chaperones are between the Hsp70s and Hsp90s. In S. cerevisiae, Hsp90 and Hsp70 orthologs (Hsp82 and Ssa1) interact with each other mediated by the tetratricopeptide repeat protein Sti1 and this interaction is enhanced by cytosolic JDPs [ 15 , 103 , 104 , 105 ]. In addition to its role in coordinating their interaction, Sti1 facilitates substrate transfer from Hsp70 to Hsp90 [ 106 ].…”

Section: Coordination Of Chaperoning Activity Across Different Fammentioning

confidence: 99%

Chaperone Networks in Fungal Pathogens of Humans

Horianopoulos

Kronstad

2021

JoF

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The heat shock proteins (HSPs) function as chaperones to facilitate proper folding and modification of proteins and are of particular importance when organisms are subjected to unfavourable conditions. The human fungal pathogens are subjected to such conditions within the context of infection as they are exposed to human body temperature as well as the host immune response. Herein, the roles of the major classes of HSPs are briefly reviewed and their known contributions in human fungal pathogens are described with a focus on Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. The Hsp90s and Hsp70s in human fungal pathogens broadly contribute to thermotolerance, morphological changes required for virulence, and tolerance to antifungal drugs. There are also examples of J domain co-chaperones and small HSPs influencing the elaboration of virulence factors in human fungal pathogens. However, there are diverse members in these groups of chaperones and there is still much to be uncovered about their contributions to pathogenesis. These HSPs do not act in isolation, but rather they form a network with one another. Interactions between chaperones define their specific roles and enhance their protein folding capabilities. Recent efforts to characterize these HSP networks in human fungal pathogens have revealed that there are unique interactions relevant to these pathogens, particularly under stress conditions. The chaperone networks in the fungal pathogens are also emerging as key coordinators of pathogenesis and antifungal drug tolerance, suggesting that their disruption is a promising strategy for the development of antifungal therapy.

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“…By contrast, Hsp90 typically functions later 11 , targeting a select set of “clients” 7,16 . Despite the differences, Hsp90 and Hsp70 share clients that are highly enriched for signaling and regulatory proteins 4,16,17 , making both chaperones important pharmaceutical targets for cancer 18,19 and neurodegenerative diseases 20–22 . Both chaperones are dynamic molecular machines with complex ATP-dependent conformational cycles that drive client binding/release.…”

Section: Mainmentioning

confidence: 99%

GR chaperone cycle mechanism revealed by cryo-EM: inactivation of GR by GR:Hsp90:Hsp70:Hop client-loading complex

Noddings

Kirschke

et al. 2020

Preprint

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Maintaining a healthy proteome is fundamental for organism survival. Integral to this are Hsp90 and Hsp70 molecular chaperones that together facilitate the folding, remodeling and maturation of Hsp90's many "client" proteins. The glucocorticoid receptor (GR) is a model client strictly dependent upon Hsp90/Hsp70 for activity. Chaperoning GR involves a cycle of inactivation by Hsp70, formation of an inactive GR:Hsp90:Hsp70:Hop "loading" complex, conversion to an active GR:Hsp90:p23 "maturation" complex, and subsequent GR release. Unfortunately, a molecular understanding of this intricate chaperone cycle is lacking for any client. Here, we report the cryo-EM structure of the GR loading complex, in which Hsp70 loads GR onto Hsp90, revealing the molecular basis of direct Hsp90/Hsp70 coordination. The structure reveals two Hsp70s--one delivering GR and the other scaffolding Hop. Unexpectedly, the Hop cochaperone interacts with all components of the complex including GR, poising Hsp90 for subsequent ATP hydrolysis. GR is partially unfolded and recognized via an extended binding pocket composed of Hsp90, Hsp70 and Hop, revealing the mechanism of GR loading and inactivation. Together with the GR maturation complex (Noddings et al., 2020), we present the first complete molecular mechanism of chaperone-dependent client remodeling, establishing general principles of client recognition, inhibition, transfer and activation.

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Intermolecular Interactions between Hsp90 and Hsp70

Cited by 40 publications

References 73 publications

Structural Communication between the E. coli Chaperones DnaK and Hsp90

Structural Communication between the E. coli Chaperones DnaK and Hsp90

Chaperone Networks in Fungal Pathogens of Humans

GR chaperone cycle mechanism revealed by cryo-EM: inactivation of GR by GR:Hsp90:Hsp70:Hop client-loading complex

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