RT Journal Article
SR Electronic
T1 Non-equilibrium protein folding and activation by ATP-driven chaperones
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.21.492947
DO 10.1101/2022.05.21.492947
A1 Huafeng Xu
YR 2022
UL http://biorxiv.org/content/early/2022/05/23/2022.05.21.492947.abstract
AB Recent experimental studies suggest that ATP-driven molecular chaperones can stabilize protein substrates in their native structures out of thermal equilibrium. The mechanism of such nonequilibrium protein folding is an open question. Based on available structural and biochemical evidence, I propose here a unifying principle that underlies the conversion of chemical energy from ATP hydrolysis to the conformational free energy associated with protein folding and activation. I demonstrate that non-equilibrium folding requires the chaperones to break at least one of four symmetry conditions. The Hsp70 and Hsp90 chaperones each breaks a different subset of these symmetries and thus they use different mechanisms for non-equilibrium protein folding. I derive an upper bound on the non-equilibrium elevation of the native concentration, which implies that non-equilibrium folding only occurs in slow-folding proteins that adopt an unstable intermediate conformation in binding to ATP-driven chaperones. Contrary to the long-held view of Anfinsen’s hypothesis that proteins fold to their conformational free energy minima, my results predict that some proteins may fold into thermodynamically unstable native structures with the assistance of ATP-driven chaperones, and that the native structures of some chaperone-dependent proteins may be shaped by their chaperone-mediated folding pathways.Competing Interest StatementThe authors have declared no competing interest.