Cracking the chaperone code through the computational microscope

IF 3.3 3区 生物学 Q3 CELL BIOLOGY
Federica Guarra , Cristiano Sciva , Giorgio Bonollo , Chiranjeevi Pasala , Gabriela Chiosis , Elisabetta Moroni , Giorgio Colombo
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引用次数: 0

Abstract

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.

通过计算显微镜破解伴侣密码。
Hsp90 合子机制在维持细胞平衡方面发挥着至关重要的作用。除了在蛋白质折叠中的传统作用外,Hsp90 还是影响健康和疾病中细胞功能的关键途径中不可或缺的一部分。Hsp90 通过大型多蛋白复合物的模块化组装来运作,其组成、稳定性和定位都能适应细胞的需要。其功能动态受配体结合和翻译后修饰(PTM)的微调。在这里,我们将讨论如何利用基于计算机的方法来解开支配 Hsp90 机制的动态、结合、PTMs 和功能之间相互影响的复杂密码。具体来说,我们概述了计算和理论方法对了解 Hsp90 功能的贡献,包括从原子层面深入了解其动力学,到阐明其与蛋白质客户、辅助伴侣和配体的相互作用机制。在这一框架下产生的知识可用于设计和开发针对特定疾病相关细胞环境中 Hsp90 的化学工具和药物。最后,我们提出了自己的观点,即如何将计算整合到高度复杂的 Hsp90 功能微调研究中,以补充实验方法,从而全面了解这一重要的伴侣系统。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Stress & Chaperones
Cell Stress & Chaperones 生物-细胞生物学
CiteScore
7.60
自引率
2.60%
发文量
59
审稿时长
6-12 weeks
期刊介绍: Cell Stress and Chaperones is an integrative journal that bridges the gap between laboratory model systems and natural populations. The journal captures the eclectic spirit of the cellular stress response field in a single, concentrated source of current information. Major emphasis is placed on the effects of climate change on individual species in the natural environment and their capacity to adapt. This emphasis expands our focus on stress biology and medicine by linking climate change effects to research on cellular stress responses of animals, micro-organisms and plants.
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