Biebl Maximilian M, Riedl Maximilian, Buchner Johannes
Center for Integrated Protein Science at the Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
Center for Integrated Protein Science at the Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
Cell Rep. 2020 Aug 25;32(8):108063. doi: 10.1016/j.celrep.2020.108063.
Heat shock protein 90 (Hsp90) is a molecular chaperone regulating the activity of diverse client proteins together with a plethora of different co-chaperones. Whether these functionally cooperate has remained enigmatic. We analyze all double mutants of 11 Saccharomyces cerevisiae Hsp90 co-chaperones in vivo concerning effects on cell physiology and the activation of specific client proteins. We find that client activation is supported by a genetic network with weak epistasis between most co-chaperones and a few modules with strong genetic interactions. These include an epistatic module regulating protein translation and dedicated epistatic networks for specific clients. For kinases, the bridging of Hsp70 and Hsp90 by Sti1/Hop is essential for activation, whereas for steroid hormone receptors, an epistatic module regulating their dwell time on Hsp90 is crucial, highlighting the specific needs of different clients. Thus, the Hsp90 system is characterized by plastic co-chaperone networks fine-tuning the conformational processing in a client-specific manner.
热休克蛋白90（Hsp90）是一种分子伴侣，它与众多不同的共伴侣一起调节多种客户蛋白的活性。这些蛋白在功能上是否协同作用一直是个谜。我们在体内分析了11种酿酒酵母Hsp90共伴侣的所有双突变体对细胞生理学的影响以及特定客户蛋白的激活情况。我们发现，客户蛋白的激活由一个遗传网络支持，大多数共伴侣之间存在弱上位性，还有一些具有强遗传相互作用的模块。这些模块包括一个调节蛋白质翻译的上位性模块以及针对特定客户蛋白的专用上位性网络。对于激酶而言，Sti1/Hop在Hsp70和Hsp90之间的桥接对于激活至关重要，而对于类固醇激素受体，一个调节它们在Hsp90上停留时间的上位性模块则至关重要，这突出了不同客户蛋白的特定需求。因此，Hsp90系统的特征是具有可塑性的共伴侣网络，以客户蛋白特异性的方式微调构象加工过程。
