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A Dynamic View of Allosteric Regulation in the Hsp70 Chaperones by J-Domain Cochaperone and Post-Translational Modifications: Computational Analysis of Hsp70 Mechanisms by Exploring Conformational Landscapes and Residue Interaction Networks.

07:00 EST 14th January 2020 | BioPortfolio

Summary of "A Dynamic View of Allosteric Regulation in the Hsp70 Chaperones by J-Domain Cochaperone and Post-Translational Modifications: Computational Analysis of Hsp70 Mechanisms by Exploring Conformational Landscapes and Residue Interaction Networks."

Structural and biochemical studies of the Hsp70 chaperones have provided the molecular view of the chaperone biochemical cycle by revealing a complex interplay between allosteric conformational states that controls the feedback loop between stimulation of the ATPase activity and the substrate release. Allosteric regulation in the Hsp70 chaperones and efficient substrate targeting are mediated by J-domain cochaperones through a dynamic interaction network controlled by the regulatory hotspots. In the current work, we have simulated conformational landscapes and residue interaction networks in the open, closed and cochaperone-bound DnaK structures. The results of this work have shown that J-domain can selectively enhance direction-specific signal propagation from the substrate binding domain to the catalytic center and promote structural environment required for ATP hydrolysis. By employing different network-based approaches, we examined the role and contribution of post-translational modifications sites in allosteric regulation of human Hsp70. The central finding of this analysis indicated that conserved phosphorylation sites localized preferentially in the nucleotide-binding domain regions are often aligned with the allosteric control points and serve as effector centers in the Hsp70. We have found that cooperation of post-translational modifications sites is based on the governing role of phosphorylation sites in dictating regulatory switching functions, while the bulk of acetylation sites can be involved in sensing the long-range signals and executing allosteric changes during the ATPase cycle. The results of this study highlight the important role of phosphorylation sites in exerting control over allosteric changes in the Hsp70. The network-centric framework for analysis of conformational dynamics and chaperone landscapes can explain a range of structural and functional experiments, providing a robust dynamic model of Hsp70 regulation by cochaperones and sites of post-translational modifications.

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Name: Journal of chemical information and modeling
ISSN: 1549-960X
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