Molecular mechanisms of chaperone-directed protein folding: Insights from atomistic simulations.
Molecular mechanisms of chaperone-directed protein folding: Insights from atomistic simulations.
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伴侣定向蛋白质折叠的分子机制：原子模拟的见解。
DOI：
10.1002/pro.4880
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Castelli M
中科院分区：
文献类型：
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作者：
Castelli M
分子伴侣是一个蛋白质家族，其中Hsp 90和Hsp 70是其不可或缺的成员，通过控制过多底物客户蛋白的折叠和激活来形成维持健康蛋白质组的必要机制。这是通过Hsp 90和Hsp 70的循环来实现的，在这些循环中，Hsp 90和Hsp 70由任务特异性共伴侣调节，处理ATP并成为经历广泛组成和构象变化的复杂网络的一部分。尽管在结构知识方面取得了令人印象深刻的进展，但调节功能组件动态的机制，它们对核苷酸的反应以及它们与客户端重塑的相关性仍然难以捉摸。在这里，我们专注于糖皮质激素受体（GR）：Hsp 90：Hsp 70：共伴侣Hop客户端加载和GR：Hsp 90：共伴侣p23客户端成熟复合物，糖皮质激素受体（GR）折叠周期中的关键组件，严格依赖于Hsp 90/Hsp 70的客户端活动。使用分子动力学模拟方法的组合，我们揭示了前所未有的细节的机制，支持这些分子伴侣机制的功能。具体来说，我们剖析了核苷酸编码的消息传递到客户端的过程，以及组装体的不同伙伴如何在加载和成熟过程中合作（预）组织部分折叠的GR。我们展示了不同的配体状态如何确定不同的动态配置文件的功能接口定义的相互作用的复合物和调节其整体的灵活性，以促进沿着的伴侣循环的进展。最后，我们还表明，GR地区从事的伴侣机器显示特殊的能量签名的折叠状态，这提高了部分展开波动的概率。从这些结果中，我们提出了一个模型，其中动态串扰出现在伴侣动力学状态和客户端交互区域的重塑之间。这个因素，再加上高度动态的性质的组件和构象的异质性，它们的相互作用，提供了在伴侣循环过程中调节不同的组件的功能的基础。
Molecular chaperones, a family of proteins of which Hsp90 and Hsp70 are integral members, form an essential machinery to maintain healthy proteomes by controlling the folding and activation of a plethora of substrate client proteins. This is achieved through cycles in which Hsp90 and Hsp70, regulated by task‐specific co‐chaperones, process ATP and become part of a complex network that undergoes extensive compositional and conformational variations. Despite impressive advances in structural knowledge, the mechanisms that regulate the dynamics of functional assemblies, their response to nucleotides, and their relevance for client remodeling are still elusive. Here, we focus on the glucocorticoid receptor (GR):Hsp90:Hsp70:co‐chaperone Hop client‐loading and the GR:Hsp90:co‐chaperone p23 client‐maturation complexes, key assemblies in the folding cycle of glucocorticoid receptor (GR), a client strictly dependent upon Hsp90/Hsp70 for activity. Using a combination of molecular dynamics simulation approaches, we unveil with unprecedented detail the mechanisms that underpin function in these chaperone machineries. Specifically, we dissect the processes by which the nucleotide‐encoded message is relayed to the client and how the distinct partners of the assemblies cooperate to (pre)organize partially folded GR during Loading and Maturation. We show how different ligand states determine distinct dynamic profiles for the functional interfaces defining the interactions in the complexes and modulate their overall flexibility to facilitate progress along the chaperone cycle. Finally, we also show that the GR regions engaged by the chaperone machinery display peculiar energetic signatures in the folded state, which enhance the probability of partial unfolding fluctuations. From these results, we propose a model where a dynamic cross‐talk emerges between the chaperone dynamics states and remodeling of client‐interacting regions. This factor, coupled to the highly dynamic nature of the assemblies and the conformational heterogeneity of their interactions, provides the basis for regulating the functions of distinct assemblies during the chaperoning cycle.