Cracking the chaperone code through the computational microscope.

Autor:	Guarra F; Department of Chemistry, University of Pavia, Pavia, Italy., Sciva C; Department of Chemistry, University of Pavia, Pavia, Italy., Bonollo G; Department of Chemistry, University of Pavia, Pavia, Italy., Pasala C; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Chiosis G; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Moroni E; Institute of Chemical Sciences and Technologies (SCITEC) - Italian National Research Council (CNR), Milano, Italy. Electronic address: elisabetta.moroni@scitec.cnr.it., Colombo G; Department of Chemistry, University of Pavia, Pavia, Italy. Electronic address: g.colombo@unipv.it.
Jazyk:	angličtina
Zdroj:	Cell stress & chaperones [Cell Stress Chaperones] 2024 Oct; Vol. 29 (5), pp. 626-640. Date of Electronic Publication: 2024 Aug 12.
DOI:	10.1016/j.cstres.2024.08.001
Abstrakt:	The heat shock protein 90 kDa (Hsp90) chaperone machinery plays a crucial role in maintaining cellular homeostasis. Beyond its traditional role in protein folding, Hsp90 is integral to key pathways influencing cellular function in health and disease. Hsp90 operates through the modular assembly of large multiprotein complexes, with their composition, stability, and localization adapting to the cell's needs. Its functional dynamics are finely tuned by ligand binding and post-translational modifications (PTMs). Here, we discuss how to disentangle the intricacies of the complex code that governs the crosstalk between dynamics, binding, PTMs, and the functions of the Hsp90 machinery using computer-based approaches. Specifically, we outline the contributions of computational and theoretical methods to the understanding of Hsp90 functions, ranging from providing atomic-level insights into its dynamics to clarifying the mechanisms of interactions with protein clients, cochaperones, and ligands. The knowledge generated in this framework can be actionable for the design and development of chemical tools and drugs targeting Hsp90 in specific disease-associated cellular contexts. Finally, we provide our perspective on how computation can be integrated into the study of the fine-tuning of functions in the highly complex Hsp90 landscape, complementing experimental methods for a comprehensive understanding of this important chaperone system. Competing Interests: Declarations of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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