Dataset Information

Dynamically Shaping Chaperones. Allosteric Modulators of HSP90 Family as Regulatory Tools of Cell Metabolism in Neoplastic Progression.

ABSTRACT: Molecular chaperones have recently emerged as fundamental regulators of salient biological routines, including metabolic adaptations to environmental changes. Yet, many of the molecular mechanisms at the basis of their functions are still unknown or at least uncertain. This is in part due to the lack of chemical tools that can interact with the chaperones to induce measurable functional perturbations. In this context, the use of small molecules as modulators of protein functions has proven relevant for the investigation of a number of biomolecular systems. Herein, we focus on the functions, interactions and signaling pathways of the HSP90 family of molecular chaperones as possible targets for the discovery of new molecular entities aimed at tuning their activity and interactions. HSP90 and its mitochondrial paralog, TRAP1, regulate the activity of crucial metabolic circuitries, making cells capable of efficiently using available energy sources, with relevant implications both in healthy conditions and in a variety of disease states and especially cancer. The design of small-molecules targeting the chaperone cycle of HSP90 and able to inhibit or stimulate the activity of the protein can provide opportunities to finely dissect their biochemical activities and to obtain lead compounds to develop novel, mechanism-based drugs.

SUBMITTER: Sanchez-Martin C

PROVIDER: S-EPMC7378685 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Dynamically Shaping Chaperones. Allosteric Modulators of HSP90 Family as Regulatory Tools of Cell Metabolism in Neoplastic Progression.

Sanchez-Martin Carlos C Serapian Stefano A SA Colombo Giorgio G Rasola Andrea A

Frontiers in oncology 20200716

Molecular chaperones have recently emerged as fundamental regulators of salient biological routines, including metabolic adaptations to environmental changes. Yet, many of the molecular mechanisms at the basis of their functions are still unknown or at least uncertain. This is in part due to the lack of chemical tools that can interact with the chaperones to induce measurable functional perturbations. In this context, the use of small molecules as modulators of protein functions has proven relev ...[more]

PMID: 32766157

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Project description:A fundamental role of the Hsp90 chaperone in regulating functional activity of diverse protein clients is essential for the integrity of signaling networks. In this work we have combined biophysical simulations of the Hsp90 crystal structures with the protein structure network analysis to characterize the statistical ensemble of allosteric interaction networks and communication pathways in the Hsp90 chaperones. We have found that principal structurally stable communities could be preserved during dynamic changes in the conformational ensemble. The dominant contribution of the inter-domain rigidity to the interaction networks has emerged as a common factor responsible for the thermodynamic stability of the active chaperone form during the ATPase cycle. Structural stability analysis using force constant profiling of the inter-residue fluctuation distances has identified a network of conserved structurally rigid residues that could serve as global mediating sites of allosteric communication. Mapping of the conformational landscape with the network centrality parameters has demonstrated that stable communities and mediating residues may act concertedly with the shifts in the conformational equilibrium and could describe the majority of functionally significant chaperone residues. The network analysis has revealed a relationship between structural stability, global centrality and functional significance of hotspot residues involved in chaperone regulation. We have found that allosteric interactions in the Hsp90 chaperone may be mediated by modules of structurally stable residues that display high betweenness in the global interaction network. The results of this study have suggested that allosteric interactions in the Hsp90 chaperone may operate via a mechanism that combines rapid and efficient communication by a single optimal pathway of structurally rigid residues and more robust signal transmission using an ensemble of suboptimal multiple communication routes. This may be a universal requirement encoded in protein structures to balance the inherent tension between resilience and efficiency of the residue interaction networks.

Dataset Information

Dynamically Shaping Chaperones. Allosteric Modulators of HSP90 Family as Regulatory Tools of Cell Metabolism in Neoplastic Progression.

Publications

Dynamically Shaping Chaperones. Allosteric Modulators of HSP90 Family as Regulatory Tools of Cell Metabolism in Neoplastic Progression.

Similar Datasets

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