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 that 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 对激酶客户的 ATP 驱动非平衡激活

分子伴侣 90-kDa 热休克蛋白 (Hsp90) 有助于后期折叠和激活多种类型的蛋白质底物（称为客户），包括许多激酶。以前的研究已经确定 Hsp90 同源二聚体通过开放和封闭构象经历 ATP 驱动的循环。在这里，我提出了一个由 Hsp90 激活客户的模型，该模型预测该循环使 Hsp90 能够使用 ATP 能量将客户从热力学平衡中推向其活性构象。我的模型假设 Hsp90 绑定的客户端可以在失活构象和激活构象之间转换。这表明辅助伴侣 Cdc37 通过区分这两种中间构象来帮助 Hsp90 激活激酶客户。我的模型做出了可通过实验测试的预测，包括调节 Hsp90 循环的逐步动力学——例如，通过各种辅助伴侣——如何影响不同客户的激活。我的模型可以告知 Hsp90 介导的蛋白质激活的客户特异性和细胞类型特异性治疗干预。