Biophysical Journal 116.3 (2019): 339a.
The heat shock protein 70 (Hsp70) chaperones, vital to the proper folding of proteins inside cells, consume ATP and require cochaperones in assisting pro- tein folding. It is unclear whether Hsp70 can utilize the free energy from ATP hydrolysis to fold a protein into a native state that is thermodynamically unsta- ble in the chaperone-free equilibrium. Here I present a model of Hsp70- mediated protein folding, which predicts that Hsp70, as a result of differential stimulation of ATP hydrolysis by its Hsp40 cochaperone, dissociates faster from a substrate in fold-competent conformations than from one in misfolding-prone conformations, thus elevating the native concentration above and suppressing the misfolded concentration below their respective equilibrium values. In contrast to the prevailing notion that Hsp70 is an unfoldase/holdase that pulls proteins out of their misfolded states, my model suggests that Hsp70 actively folds proteins into the native state. My model quantitatively reproduces experimental refolding kinetics, predicts how modulations of the Hsp70/Hsp40 chaperone system affect protein folding, and suggests new approaches to regu- lating cellular protein quality. The key prediction of my model, that Hsp70 can use ATP energy for non-equilibrium stabilization of native proteins, is in agree- ment with recent experimental results. I propose additional new experiments to further test my model.Biophysical Journal