A dynamic view of ATP-coupled functioning cycle of Hsp90 N-terminal domain.
A dynamic view of ATP-coupled functioning cycle of Hsp90 N-terminal domain.
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Hsp90 N 端结构域 ATP 偶联功能循环的动态视图
DOI：
10.1038/srep09542
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发表时间：
2015-04-13
影响因子：
4.6
通讯作者：
Zhang N
中科院分区：
文献类型：
--
作者：
Zhang H;Zhou C;Chen W;Xu Y;Shi Y;Wen Y;Zhang N
热休克蛋白90(Hsp90)是参与多种细胞过程的重要伴侣蛋白之一。Hsp90的伴侣功能与其N-末端结构域呈现的ATPase活性密切相连。然而，Hsp90依赖于ATP的工作周期的分子机制仍不完全清楚。在这项研究中，我们利用核磁共振技术研究了Hsp90N-末端结构域在其自由和AMPPCP(ATP类似物)或ADP结合状态下的结构特征和动力学行为。我们发现，虽然AMPPCP和ADP结合在Hsp90上几乎相同的区域，但对关键结构元件的动力学行为有显著不同的影响。AMPPCP结合通过促进LID片段(A111-G135)内那些残基(A117-A141)的慢动作特征构象交换促进Hsp90活性同源二聚体的形成，而ADP结合通过增加LID片段及其周围区域的构象刚性使Hsp90保持在非活性状态。基于我们的研究结果，提出了Hsp90依赖于ATP的功能循环的动态工作模型。
Heat-shock protein 90 (Hsp90) is one of the most important chaperones involved in multiple cellular processes. The chaperoning function of Hsp90 is intimately coupled to the ATPase activity presented by its N-terminal domain. However, the molecular mechanism for the ATP-dependent working cycle of Hsp90 is still not fully understood. In this study, we use NMR techniques to investigate the structural characteristics and dynamic behaviors of Hsp90 N-terminal domain in its free and AMPPCP (ATP analogue) or ADP-bound states. We demonstrated that although AMPPCP and ADP bind to almost the same region of Hsp90, significantly different effects on the dynamics behaviors of the key structural elements were observed. AMPPCP binding favors the formation of the active homodimer of Hsp90 by enhancing the slow-motion featured conformational exchanges of those residues (A117–A141) within the lid segment (A111–G135) and around region, while ADP binding keeps Hsp90 staying at the inactive state by increasing the conformational rigidity of the lid segment and around region. Based on our findings, a dynamic working model for the ATP-dependent functioning cycle of Hsp90 was proposed.
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