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首页> 外文期刊>Journal of Molecular Biology >Cross-monomer substrate contacts reposition the Hsp90 N-terminal domain and prime the chaperone activity
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Cross-monomer substrate contacts reposition the Hsp90 N-terminal domain and prime the chaperone activity

机译：跨单体底物触点重新定位Hsp90 N末端结构域并启动分子伴侣活性

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摘要

The ubiquitous molecular chaperone Hsp90 plays a critical role in substrate protein folding and maintenance, but the functional mechanism has been difficult to elucidate. In previous work, a model Hsp90 substrate revealed an activation process in which substrate binding accelerates a large open/closed conformational change required for ATP hydrolysis by Hsp90. While this could serve as an elegant mechanism for conserving ATP usage for productive interactions on the substrate, the structural origin of substrate-catalyzed Hsp90 conformational changes is unknown. Here, we find that substrate binding affects an intrinsically unfavorable rotation of the Hsp90 N-terminal domain (NTD) relative to the middle domain (MD) that is required for closure. We identify an MD substrate binding region on the interior cleft of the Hsp90 dimer and show that a secondary set of substrate contacts drives an NTD orientation change on the opposite monomer. These results suggest an Hsp90 activation mechanism in which cross-monomer contacts mediated by a partially structured substrate prime the chaperone for its functional activity.
机译：普遍存在的分子伴侣Hsp90在底物蛋白折叠和维持中起着关键作用，但是其功能机制一直难以阐明。在以前的工作中，模型Hsp90底物揭示了一个激活过程，其中底物结合加速了Hsp90水解ATP所需的大的打开/关闭构象变化。虽然这可以作为节省用于底物上的生产性相互作用的ATP用量的优良机制，但底物催化的Hsp90构象变化的结构起源尚不清楚。在这里，我们发现底物结合影响Hsp90 N末端域（NTD）相对于封闭所需的中间域（MD）的固有不利旋转。我们在Hsp90二聚体的内部裂口上确定了MD底物结合区，并显示了第二组底物接触驱动了相反单体上的NTD方向变化。这些结果提示了Hsp90激活机制，其中由部分结构化的底物介导的交叉单体接触使伴侣分子发挥其功能活性。

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