The molecular chaperone 90-kDa heat-shock protein (Hsp90) assists the late-stage folding and activation of diverse types of protein substrates (called clients), including many kinases. Previous studies have established that the Hsp90 homodimer undergoes an ATP-driven cycle through open and closed conformations. Here I propose a model of client activation by Hsp90, which predicts that this cycle enables Hsp90 to use ATP energy to drive a client out of thermodynamic equilibrium toward its active conformation. My model assumes that an Hsp90-bound client can transition between a deactivating conformation and an activating conformation. It suggests that the cochaperone Cdc37 aids Hsp90 to activate kinase clients by differentiating between these two intermediate conformations. My model makes experimentally testable predictions, including how modulating the stepwise kinetics of the Hsp90 cycle--for example, by various cochaperones--affects the activation of different clients. My model may inform client-specific and cell-type-specific therapeutic intervention of Hsp90-mediated protein activation.

中文翻译：

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分子伴侣Hsp90的ATP驱动的激酶客户的非平衡活化

分子伴侣90 kDa热休克蛋白（Hsp90）有助于后期折叠和激活包括许多激酶在内的各种类型的蛋白底物（称为客户）。先前的研究已经确定，Hsp90同型二聚体通过开放和闭合构象经历ATP驱动的循环。在这里，我提出了一个由Hsp90激活客户的模型，该模型预测此循环使Hsp90能够使用ATP能量将客户从热力学平衡中驱逐出其主动构象。我的模型假定绑定Hsp90的客户端可以在停用构象和激活构象之间进行转换。它表明，伴侣蛋白Cdc37通过区分这两个中间构象来帮助Hsp90激活激酶客户。我的模型做出了实验可检验的预测，包括如何调节Hsp90循环的逐步动力学（例如通过各种辅酶伴侣）如何影响不同客户的激活。我的模型可能会为Hsp90介导的蛋白质激活提供特定于客户和特定于细胞类型的治疗干预。