Nature Structural & Molecular Biology ( IF 12.5 ) Pub Date : 2024-06-18 , DOI: 10.1038/s41594-024-01337-z Xiaozhan Qu 1, 2, 3, 4 , Shuo Zhao 1, 2, 3, 4 , Chanjuan Wan 4 , Lei Zhu 5 , Tuo Ji 1, 2, 3, 4 , Paolo Rossi 6 , Junfeng Wang 5 , Charalampos G Kalodimos 6 , Chao Wang 1, 2, 3, 4, 7 , Weiya Xu 1, 2, 3, 4, 7 , Chengdong Huang 1, 2, 3, 4, 7
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Molecular chaperone heat shock protein 90 (Hsp90) is a ubiquitous regulator that fine-tunes and remodels diverse client proteins, exerting profound effects on normal biology and diseases. Unraveling the mechanistic details of Hsp90’s function requires atomic-level insights into its client interactions throughout the adenosine triphosphate-coupled functional cycle. However, the structural details of the initial encounter complex in the chaperone cycle, wherein Hsp90 adopts an open conformation while engaging with the client, remain elusive. Here, using nuclear magnetic resonance spectroscopy, we determined the solution structure of Hsp90 in its open state, bound to a disordered client. Our findings reveal that Hsp90 uses two distinct binding sites, collaborating synergistically to capture discrete hydrophobic segments within client proteins. This bipartite interaction generates a versatile complex that facilitates rapid conformational sampling. Moreover, our investigations spanning various clients and Hsp90 orthologs demonstrate a pervasive mechanism used by Hsp90 orthologs to accommodate the vast array of client proteins. Collectively, our work contributes to establish a unified conceptual and mechanistic framework, elucidating the intricate interplay between Hsp90 and its clients.
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Hsp90 动态陪伴紊乱客户的结构基础
分子伴侣热休克蛋白 90 (Hsp90) 是一种普遍存在的调节因子,可以微调和重塑不同的客户蛋白,对正常生物学和疾病产生深远影响。解开 Hsp90 功能的机制细节需要在整个三磷酸腺苷偶联功能循环中对其客户相互作用进行原子水平的了解。然而,伴侣循环中初始遭遇复合体的结构细节仍然难以捉摸,其中 Hsp90 在与客户接触时采用开放构象。在这里,我们使用核磁共振波谱确定了 Hsp90 在开放状态下的溶液结构,该结构与无序客户结合。我们的研究结果表明,Hsp90 使用两个不同的结合位点,协同捕获客户蛋白内离散的疏水片段。这种二分相互作用产生了一种多功能复合物,有利于快速构象采样。此外,我们对各种客户和 Hsp90 直系同源物的研究表明,Hsp90 直系同源物使用普遍的机制来适应大量客户蛋白。总的来说,我们的工作有助于建立一个统一的概念和机制框架,阐明 Hsp90 与其客户之间复杂的相互作用。