Dissection of the ATP-induced conformational cycle of the molecular chaperone Hsp90
Dissection of the ATP-induced conformational cycle of the molecular chaperone Hsp90
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DOI：
10.1038/nsmb.1565
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发表时间：
2009-03-01
影响因子：
16.8
通讯作者：
Buchner, Johannes
中科院分区：
文献类型：
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作者：
Hessling, Martin;Richter, Klaus;Buchner, Johannes
分子伴侣热休克蛋白 90 (Hsp90) 将 ATP 水解与构象变化结合起来，驱动底物激活所需的反应循环。最近的结构分析提供了 Hsp90 的开放和关闭状态的快照，这标志着这些变化的起点和终点。利用荧光共振能量转移（FRET），我们从动力学角度剖析了循环并识别了途径上的中间体。构象转变比 ATP 水解步骤慢几个数量级，因此是反应周期中的限制事件。此外，这些结构变化可以受到共伴侣分子的严格调控，被 Sti1 完全抑制或被 Aha1 加速。事实上，即使在没有核苷酸的情况下，Aha1 也会诱导 Hsp90 重排，从而加速构象循环。 Hsp90 循环的这种全面重建定义了通过不同中间体的受控进程，这些中间体可以通过构象敏感的辅助伴侣进行调节。 (c) 2009 Nature America, Inc. 保留所有权利。
The molecular chaperone heat-shock protein 90 (Hsp90) couples ATP hydrolysis to conformational changes driving a reaction cycle that is required for substrate activation. Recent structural analysis provided snapshots of the open and closed states of Hsp90, which mark the starting and end points of these changes. Using fluorescence resonance energy transfer ( FRET), we dissected the cycle kinetically and identified the intermediates on the pathway. The conformational transitions are orders of magnitude slower than the ATP-hydrolysis step and thus are the limiting events during the reaction cycle. Furthermore, these structural changes can be tightly regulated by cochaperones, being completely inhibited by Sti1 or accelerated by Aha1. In fact, even in the absence of nucleotide, Aha1 induces Hsp90 rearrangements that speed up the conformational cycle. This comprehensive reconstitution of the Hsp90 cycle defines a controlled progression through distinct intermediates that can be modulated by conformation-sensitive cochaperones. (c) 2009 Nature America, Inc. All rights reserved.