Non-Equilibrium Protein Folding and Activation by ATP-Driven Chaperones

Abstract

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 non-equilibrium 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 break 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.

Hsp90 and Associated Co-Chaperones of the Malaria Parasite

“…Furthermore, the co-evolution of PfHsp90 and the kinome could have resulted in reduced dependency on a canonical Cdc37 for kinase activation. Indeed, there is evidence that Hsp90 may be able to activate kinases in the absence of Cdc37 [ 121 , 122 ]. Importantly, no study has demonstrated that P. falciparum kinases require PfHsp90 in a mechanism analogous to their yeast and human orthologs.…”

An Editorial on the Special Issue ‘Hsp90 Structure, Mechanism and Disease’

“…The ‘Editor’s Choice’ article by Haufeng [ 16 ] discusses whether proteins always fold to a free-energy minimum or whether they can be maintained by energy-consuming processes in functional conformations with elevated free energies. The common view is that chaperones accelerate the kinetics of the folding process so that substrates reach their free-energy minimum.…”