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Elucidating the mechanism of substrate recognition by the bacterial Hsp90 molecular chaperone

机译：阐明细菌Hsp90分子伴侣的底物识别机制

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摘要

Hsp90 is a conformationally dynamic molecular chaperone known to promote the folding and activation of a broad array of protein substrates ("clients"). Hsp90 is believed to preferentially interact with partially folded substrates, and it has been hypothesized that the chaperone can significantly alter substrate structure as a mechanism to alter the substrate functional state. However, critically testing the mechanism of substrate recognition and remodeling by Hsp90 has been challenging. Using a partially folded protein as a model system, we find that the bacterial Hsp90 adapts its conformation to the substrate, forming a binding site that spans the middle and C-terminal domains of the chaperone. Cross-linking and NMR measurements indicate that Hsp90 binds to a large partially folded region of the substrate and significantly alters both its local and long-range structure. These findings implicate Hsp90's conformational dynamics in its ability to bind and remodel partially folded proteins. Moreover, native-state hydrogen exchange indicates that Hsp90 can also interact with partially folded states only transiently populated from within a thermodynamically stable, native-state ensemble. These results suggest a general mechanism by which Hsp90 can recognize and remodel native proteins by binding and remodeling partially folded states that are transiently sampled from within the native ensemble.
机译：Hsp90是构象动力学的分子伴侣，已知其可促进多种蛋白质底物（“客户”）的折叠和活化。 Hsp90被认为优先与部分折叠的底物相互作用，并且已经假设伴侣分子可以显着改变底物结构作为改变底物功能状态的机制。然而，通过Hsp90严格测试底物识别和重塑的机制一直具有挑战性。使用部分折叠的蛋白质作为模型系统，我们发现细菌Hsp90使其构象适应底物，形成跨伴侣分子中部和C端结构域的结合位点。交联和NMR测量表明Hsp90与底物的较大部分折叠区域结合，并显着改变其局部和远距离结构。这些发现暗示Hsp90的结合和重塑部分折叠蛋白能力的构象动力学。此外，天然氢交换表明Hsp90也可以与仅在热力学稳定的天然状态集合中短暂填充的部分折叠状态相互作用。这些结果表明，Hsp90可以通过结合和重塑部分折叠的状态来识别和重塑天然蛋白质的一般机制，该折叠状态是从天然集合中瞬时采样的。

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