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克里奥-EM揭示了Hsp90和FKBP免疫蛋白如何共同调节葡萄糖皮质体受体

Chari M Noddings¹, Jill L Johnson², David A Agard³

¹Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.

Nature structural & molecular biology

|November 9, 2023

概括

热冲击蛋白90 (Hsp90) 和其辅伴蛋白FKBP51和FKBP52调节葡萄糖皮质体受体 (GR). 结构研究揭示了FKBP52如何增强GR活动,FKBP51如何抑制GR活动,澄清了它们在GR成熟中的作用.

科学领域:

分子生物学分子生物学
结构生物学是结构生物学.
蜂信号传输是如何进行的

背景情况:

热冲击蛋白90 (Hsp90) 是一个关键的分子伴侣,对于许多客户蛋白的正确折叠和激活至关重要,包括葡萄糖皮质体受体 (GR).
众所周知,协伴蛋白FKBP51和FKBP52在体内对抗调节GR活性,但潜在的分子机制尚不清楚.

研究的目的:

阐明FKBP51和FKBP52与Hsp90陪伴机器相互作用以调节葡萄糖皮质体受体 (GR) 活性的分子机制.
确定FKBP51和FKBP52在GR函数中的对立作用的结构基础.

主要方法:

低温电子显微镜 (cryo-EM) 用于确定与Hsp90复合的人类GR的高分辨率结构,以及FKBP52或FKBP51.
进行了体外和体内测试,以评估这些相互作用对GR活性的功能后果.

主要成果:

3.01 Å的冷-EM结构显示,FKBP52直接与活性GR:Hsp90复合体结合,在体外和体内加强GR活性.
一个3.23 Å的冷-EM结构表明,FKBP51与FKBP52在与GR:Hsp90复合体结合方面竞争,作为一种强大的对手.
这些发现说明了FKBP51和FKBP52如何差异地集成到GR陪伴循环中.

结论:

通过直接激活GR:Hsp90复合体,FKBP52充当激活剂,促进GR成熟.
FKBP51通过阻止FKBP52结合,从而抑制GR成熟而起到对抗作用.
该研究提供了详细的分子和结构理解,这些辅助器如何动态调节Hsp90辅助器循环,以激活GR和功能.

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