Biophysical Journal 119.8 (2020): 1538-1549.
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 kinase client out of thermodynamic equilibrium toward its active conformation. My model is founded on a structural feature of the closed Hsp90 dimer that allows the bound client to transition between two hypothetical intermediate conformations, one folding to the inactive conformation and the other to the active conformation. It suggests that cochaperone Cdc37 aids Hsp90 to activate kinases by differentiating between the deactivating and the activating intermediate conformations. My model makes experimentally testable predictions, such as how modulating the kinetics of different steps in the Hsp90 cycle—for example, by various cochaperones—affects the activation of its clients. It may aid the rational design of therapeutic intervention of Hsp90-mediated protein activation.Biophysical Journal