Visualizing the Dynamics of a Protein Folding Machinery: The Mechanism of Asymmetric ATP Processing in Hsp90 and its Implications for Client Remodelling

D’Annessa, Ilda; Moroni, Elisabetta; Colombo, Giorgio

doi:10.1016/j.jmb.2020.166728

Cited by 10 publications

(11 citation statements)

References 66 publications

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“…By simulating the effect of cochaperones and client proteins on signal transmission in the Hsp90 chaperone system, we suggested that Hsp90 interactions may be controlled by the clusters of regulatory control points that are assembled in structural communication spines that mediate long-range interactions in the Hsp90 chaperone . An allosteric mechanism of asymmetric ATP binding in the Hsp90 and its implications for client remodeling was recently reported, showing the existence of regulatory control centers acting over the long-range to modulate chaperone function . In our latest study, we simulated the cryo-EM structure of the Hsp90–Hsp70–Hop–GR client complex and employed perturbation-based network modeling methods to show that the Hsp90 interactions can be governed by two allosteric residue clusters that exploit the intrinsically wired Hsp70 allostery to mediate integration of the Hsp70-bound client into the Hsp90 chaperone system …”

Section: Introductionmentioning

confidence: 99%

Conformational Dynamics and Mechanisms of Client Protein Integration into the Hsp90 Chaperone Controlled by Allosteric Interactions of Regulatory Switches: Perturbation-Based Network Approach for Mutational Profiling of the Hsp90 Binding and Allostery

Verkhivker

2022

J. Phys. Chem. B

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Understanding the allosteric mechanisms of the Hsp90 chaperone interactions with cochaperones and client protein clientele is fundamental to dissect activation and regulation of many proteins. In this work, atomistic simulations are combined with perturbation-based approaches and dynamic network modeling for a comparative mutational profiling of the Hsp90 binding and allosteric interaction networks in the three Hsp90 maturation complexes with FKBP51 and P23 cochaperones and the glucocorticoid receptor (GR) client. The conformational dynamics signatures of the Hsp90 complexes and dynamics fluctuation analysis revealed how the intrinsic plasticity of the Hsp90 dimer can be modulated by cochaperones and client proteins to stabilize the closed dimer state required at the maturation stage of the ATPase cycle. In silico deep mutational scanning of the protein residues characterized the hot spots of protein stability and binding affinity in the Hsp90 complexes, showing that binding hot spots may often coincide with the regulatory centers that modulate dynamic allostery in the Hsp90 dimer. We introduce a perturbation-based network approach for mutational scanning of allosteric residue potentials and characterize allosteric switch clusters that control mechanism of cochaperone-dependent client recognition and remodeling by the Hsp90 chaperone. The results revealed a conserved network of allosteric switches in the Hsp90 complexes that allow cochaperones and GR protein to become integrated into the Hsp90 system by anchoring to the conformational switch points in the functional Hsp90 regions. This study suggests that the Hsp90 binding and allostery may operate under a regulatory mechanism in which activation or repression of the Hsp90 activity can be pre-encoded in the allosterically regulated Hsp90 dimer motions. By binding directly to the conformational switch centers on the Hsp90, cochaperones and interacting proteins can efficiently modulate the allosteric interactions and long-range communications required for client remodeling and activation.

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Section: Introductionmentioning

confidence: 99%

Conformational Dynamics and Mechanisms of Client Protein Integration into the Hsp90 Chaperone Controlled by Allosteric Interactions of Regulatory Switches: Perturbation-Based Network Approach for Mutational Profiling of the Hsp90 Binding and Allostery

Verkhivker

2022

J. Phys. Chem. B

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“…Next, to expose the aminoacids whose coordination patterns are most responsive (in a quantitative and statistically significant way) to the presence of 5, we used a statistical approach based on F-tests, which we recently implemented. 62 In summary, the two distance fluctuation matrices appearing on the left-hand side of The F-ratio is the ratio between two mean sum of squares (i.e. the sum of square deviations of a set of samples with respect to their average or with respect to a predicted value, divided by the number of degrees of freedom, v).…”

Section: Resultsmentioning

confidence: 99%

Protein Allostery and Ligand Design: Computational Design Meets Experiments to Discover Novel Chemical Probes

Triveri

Sánchez-Martín

Torielli

et al. 2022

Journal of Molecular Biology

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“…Despite the wealth of information on Grp94, molecular details of the effect of nucleotide hydrolysis on the active site, signal transduction, and dynamics are still elusive. A number of computational studies on Hsp90s have been successful in revealing internal dynamics and communication networks based on nucleotide, cochaperones, and client protein binding. − While prior computational research on Hsp90 has yielded valuable insights into protein dynamics, earlier studies on Grp94 focused on the relaxed structure , that represents the posthydrolysis state. This conformation is nearly identical when either ADP or no nucleotide are bound. , In this study, we used multiscale dynamics to probe the effect of nucleotide hydrolysis and the allosteric wiring within Grp94’s closed, catalytically active conformation.…”

Section: Introductionmentioning

confidence: 99%

Insight into the Nucleotide Based Modulation of the Grp94 Molecular Chaperone Using Multiscale Dynamics

Alao,

Obaseki,

Amankwah

et al. 2023

J. Phys. Chem. B

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Grp94, an ER-localized molecular chaperone, is required for the folding and activation of many membrane and secretory proteins. Client activation by Grp94 is mediated by nucleotide and conformational changes. In this work, we aim to understand how microscopic changes from nucleotide hydrolysis can potentiate large-scale conformational changes of Grp94. We performed all-atom molecular dynamics simulations on the ATP-hydrolysis competent state of the Grp94 dimer in four different nucleotide bound states. We found that Grp94 was the most rigid when ATP was bound. ATP hydrolysis or nucleotide removal enhanced mobility of the N-terminal domain and ATP lid, resulting in suppression of interdomain communication. In an asymmetric conformation with one hydrolyzed nucleotide, we identified a more compact state, similar to experimental observations. We also identified a potential regulatory role of the flexible linker, as it formed electrostatic interactions with the Grp94 M-domain helix near the region where BiP is known to bind. These studies were complemented with normal-mode analysis of an elastic network model to investigate Grp94’s large-scale conformational changes. SPM analysis identified residues that are important in signaling conformational change, many of which have known functional relevance in ATP coordination and catalysis, client binding, and BiP binding. Our findings suggest that ATP hydrolysis in Grp94 alters allosteric wiring and facilitates conformational changes.

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Visualizing the Dynamics of a Protein Folding Machinery: The Mechanism of Asymmetric ATP Processing in Hsp90 and its Implications for Client Remodelling

Cited by 10 publications

References 66 publications

Conformational Dynamics and Mechanisms of Client Protein Integration into the Hsp90 Chaperone Controlled by Allosteric Interactions of Regulatory Switches: Perturbation-Based Network Approach for Mutational Profiling of the Hsp90 Binding and Allostery

Conformational Dynamics and Mechanisms of Client Protein Integration into the Hsp90 Chaperone Controlled by Allosteric Interactions of Regulatory Switches: Perturbation-Based Network Approach for Mutational Profiling of the Hsp90 Binding and Allostery

Protein Allostery and Ligand Design: Computational Design Meets Experiments to Discover Novel Chemical Probes

Insight into the Nucleotide Based Modulation of the Grp94 Molecular Chaperone Using Multiscale Dynamics

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