Structure, Function, and Regulation of the Hsp90 Machinery
Structure, Function, and Regulation of the Hsp90 Machinery
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DOI：
10.1101/cshperspect.a034017
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发表时间：
2019-09-01
影响因子：
7.2
通讯作者：
Buchner, Johannes
中科院分区：
文献类型：
--
作者：
Biebl, Maximilian M.;Buchner, Johannes
热休克蛋白90（Hsp90）是一种分子伴侣，参与多种底物（“客户”）的成熟，包括蛋白激酶、转录因子和E3泛素连接酶，将Hsp90定位为细胞蛋白质稳态的中心调节剂。热休克蛋白90在其ATP酶循环过程中经历大的构象变化。通过胞质Hsp90对客户的处理由一组影响客户募集、Hsp90 ATP酶功能或Hsp90中的构象重排的辅伴侣辅助。由于Hsp90在调节中枢细胞通路中的重要性，正在开发用于在疾病（例如癌症和神经变性）中药理学抑制Hsp90机制的策略。在这篇综述中，我们总结了最近的结构和机制的进展，在定义的功能的细胞器特异性和胞质Hsp90，包括个别cochaperones的成熟的影响，特定的客户端和客户端的复合物，以及利用Hsp90作为药物靶点的方式。
Heat shock protein 90 (Hsp90) is a molecular chaperone involved in the maturation of a plethora of substrates ("clients"), including protein kinases, transcription factors, and E3 ubiquitin ligases, positioning Hsp90 as a central regulator of cellular proteostasis. Hsp90 undergoes large conformational changes during its ATPase cycle. The processing of clients by cytosolic Hsp90 is assisted by a cohort of cochaperones that affect client recruitment, Hsp90 ATPase function or conformational rearrangements in Hsp90. Because of the importance of Hsp90 in regulating central cellular pathways, strategies for the pharmacological inhibition of the Hsp90 machinery in diseases such as cancer and neurodegeneration are being developed. In this review, we summarize recent structural and mechanistic progress in defining the function of organelle-specific and cytosolic Hsp90, including the impact of individual cochaperones on the maturation of specific clients and complexes with clients as well as ways of exploiting Hsp90 as a drug target.