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.
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