Glucocorticoid receptor function regulated by coordinated action of the Hsp90 and Hsp70 chaperone cycles.
Glucocorticoid receptor function regulated by coordinated action of the Hsp90 and Hsp70 chaperone cycles.
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DOI：
10.1016/j.cell.2014.04.038
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发表时间：
2014-06-19
期刊：
影响因子：
64.5
通讯作者：
Agard DA
中科院分区：
文献类型：
--
作者：
Kirschke E;Goswami D;Southworth D;Griffin PR;Agard DA
糖皮质激素受体（GR），像许多信号蛋白，依赖于热休克蛋白90分子伴侣在体内的功能。虽然体内配体结合需要Hsp90，但纯化的apoGR能够结合配体，而不受Hsp90的增强。我们发现，热休克蛋白70，已知促进客户端交付热休克蛋白90，通过部分解折叠，而热休克蛋白90逆转这种失活的GR失活。完全恢复配体结合需要ATP水解热休克蛋白90和HOP和p23辅伴侣。令人惊讶的是，来自Hsp90 ATP水解的能量似乎调节来自Hsp70的客户端转移，可能是通过两个伴侣的ATP循环的偶联。这种耦合体现在GR：Hsp70：Hsp90：HOP复合物中Hsp90和Hsp70之间的新型接触中，通过cryoEM成像。虽然从Hsp70释放的GR易于聚集，但从Hsp90释放可保护GR免于聚集并增强其配体亲和力。总之，这说明了协调的伴侣相互作用如何增强稳定性，功能和调节。
The glucocorticoid receptor (GR), like many signaling proteins, depends on the Hsp90 molecular chaperone for in vivo function. Although Hsp90 is required for ligand binding in vivo, purified apoGR is capable of binding ligand with no enhancement from Hsp90. We reveal that Hsp70, known to facilitate client delivery to Hsp90, inactivates GR through partial unfolding, while Hsp90 reverses this inactivation. Full recovery of ligand binding requires ATP hydrolysis on Hsp90 and the HOP and p23 cochaperones. Surprisingly, energy from Hsp90 ATP hydrolysis appears to regulate client transfer from Hsp70, likely through a coupling of the two chaperone’s ATP cycles. Such coupling is embodied in novel contacts between Hsp90 and Hsp70 in the GR:Hsp70:Hsp90:HOP complex imaged by cryoEM. While GR released from Hsp70 is aggregation prone, release from Hsp90 protects GR from aggregation and enhances its ligand affinity. Together, this illustrates how coordinated chaperone interactions can enhance stability, function and regulation.
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