Importance of cycle timing for the function of the molecular chaperone Hsp90

Zierer, Bettina K.; Rübbelke, Martin; Tippel, Franziska; Madl, Tobias; Schopf, Florian H.; Rutz, Daniel; Richter, Klaus; Sattler, Michael; Büchner, Johannes

doi:10.1038/nsmb.3305

Cited by 83 publications

(101 citation statements)

References 52 publications

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“…Indeed, mutants of Hsp90 have been reported that only allow the delayed hydrolysis of a single ATP molecule, but which still retain the capability to fold substrates. 63 We mention that also in the ATP simulations an initial increase in M-domain RMSD to ∼ 0.4 nm takes place at similar times, followed by a delayed jump to a value similar to the one in the ADP simulations at ca. 300 ns.…”

Section: Resultssupporting

confidence: 55%

Hierarchical coupling between ATP hydrolysis and Hsp90’s client binding site

Wolf

Sohmen

Hellenkamp

et al. 2020

Preprint

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I.ABSTRACTSeveral indicators for a signal propagation from a binding site to a distant functional site have been found in the Hsp90 dimer. Here we determined a time-resolved pathway from ATP hydrolysis to changes in a distant folding substrate binding site. This was possible by combining single-molecule fluorescence-based methods with extensive atomistic nonequilibrium molecular dynamics simulations. We find that hydrolysis of one ATP effects a structural asymmetry in the full Hsp90 dimer that leads to the collapse of a central folding substrate binding site. Arg380 is the major mediator in transferring structural information from the nucleotide to the substrate binding site. This allosteric process occurs via hierarchical dynamics that involve timescales from picoto milliseconds and length scales from Ångstroms to several nanometers. We presume that similar hierarchical mechanisms are fundamental for information transfer through many other proteins.

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Section: Resultssupporting

confidence: 55%

Hierarchical coupling between ATP hydrolysis and Hsp90’s client binding site

Wolf

Sohmen

Hellenkamp

et al. 2020

Preprint

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“…After the first hydrolysis step, the Hsp90 dimer was suggested to undergo a flip into a closed asymmetric state, followed by a second hydrolysis event. Site-directed mutagenesis experiments identified several residues involved in the ATPase reaction: Glu-33 of the yeast Hsp90 is important for the ATP-hydrolysis reaction, as the E33A variant is able to bind ATP, but not to hydrolyse it 10,12,13 . Moreover, the R380A variant has a substantially lowered ATPase activity in comparison with the wild-type (WT) enzyme 4,13 and N37A prevents Hsp90 from binding ATP due to loss of the catalytically important Mg 2+ ion (Fig.…”

mentioning

confidence: 99%

Conformational dynamics modulate the catalytic activity of the molecular chaperone Hsp90

et al. 2020

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The heat shock protein 90 (Hsp90) is a molecular chaperone that employs the free energy of ATP hydrolysis to control the folding and activation of several client proteins in the eukaryotic cell. To elucidate how the local ATPase reaction in the active site couples to the global conformational dynamics of Hsp90, we integrate here large-scale molecular simulations with biophysical experiments. We show that the conformational switching of conserved ion pairs between the N-terminal domain, harbouring the active site, and the middle domain strongly modulates the catalytic barrier of the ATP-hydrolysis reaction by electrostatic forces. Our combined findings provide a mechanistic model for the coupling between catalysis and protein dynamics in Hsp90, and show how long-range coupling effects can modulate enzymatic activity.

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“…Whereas the rate of TRAP1 ATP hydrolysis does not influence its role in OXPHOS regulation, the TRAP1 IP-MS data described in this study show that the ATP hydrolysis rate does affect TRAP1 interactions with other non-chaperone proteins. While the binding of major TRAP1 interactors such as the molecular chaperones mtHSP70 and HSP60 remains unaffected by the ATPase activity of TRAP1, the binding of most non-chaperone interactors, similarly to what has been reported for cytosolic HSP90 interactors [42], is inversely correlated with TRAP1 ATPase activity.…”

Section: Discussionmentioning

confidence: 70%

“…This finding strongly suggests that the ATPase activity of TRAP1 is not essential for OXPHOS regulation. This is reminiscent of relatively recent findings with cytosolic HSP90 indicating that the rate of ATP hydrolysis does not correlate with the ability of this molecular chaperone to support yeast viability [42], while ATP binding is absolutely essential [24, 26, 42].…”

Section: Discussionmentioning

confidence: 89%

The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in maintaining mitochondrial metabolic homeostasis

Joshi

Dai

Lee

et al. 2019

Preprint

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BackgroundThe molecular chaperone TRAP1, the mitochondrial isoform of cytosolic HSP90, remains poorly understood with respect to its pivotal role in the regulation of mitochondrial metabolism. Most studies have found it to be an inhibitor of mitochondrial oxidative phosphorylation (OXPHOS) and an inducer of the Warburg phenotype of cancer cells. However, others have reported the opposite and there is no consensus on the relevant TRAP1 interactors. This calls for a more comprehensive analysis of the TRAP1 interactome and of how TRAP1 and mitochondrial metabolism mutually affect each other.ResultsWe show that the disruption of the gene for TRAP1 in a panel of cell lines dysregulates OXPHOS by a metabolic rewiring that induces the anaplerotic utilization of glutamine metabolism to replenish TCA cycle intermediates. Restoration of wild-type levels of OXPHOS requires full-length TRAP1. Whereas the TRAP1 ATPase activity is dispensable for this function, it modulates the interactions of TRAP1 with various mitochondrial proteins. Quantitatively by far the major interactors of TRAP1 are the mitochondrial chaperones mtHSP70 and HSP60. However, we find that the most stable stoichiometric TRAP1 complex is a TRAP1 tetramer, whose levels change in response to both a decline or an increase in OXPHOS.ConclusionsOur work provides a roadmap for further investigations of how TRAP1 and its interactors such as the ATP synthase regulate cellular energy metabolism. Our results highlight that TRAP1 function in metabolism and cancer cannot be understood without a focus on TRAP1 tetramers as potentially the most relevant functional entity.

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Importance of cycle timing for the function of the molecular chaperone Hsp90

Cited by 83 publications

References 52 publications

Hierarchical coupling between ATP hydrolysis and Hsp90’s client binding site

Hierarchical coupling between ATP hydrolysis and Hsp90’s client binding site

Conformational dynamics modulate the catalytic activity of the molecular chaperone Hsp90

The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in maintaining mitochondrial metabolic homeostasis

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