The folding landscape of proteins can change during evolution with the accumulation of mutations that may introduce entropic or enthalpic barriers in the protein folding pathway, making it a possible substrate of molecular chaperones in vivo. Can the nature of such physical barriers of folding dictate the feasibility of chaperone-assistance? To address this, we have simulated the evolutionary step to chaperone-dependence keeping GroEL/ES as the target chaperone and GFP as a model protein in an unbiased screen.We find that the mutation conferring GroEL/ES dependence in vivo and in vitro encode an entropic trap in the folding pathway rescued by the chaperonin. Additionally, GroEL/ES can edit the formation of non-native contacts similar to DnaK/J/E machinery. However, this capability is not utilized by the substrates in vivo. As a consequence, GroEL/ES caters to buffer mutations that predominantly cause entropic traps, despite possessing the capacity to edit both enthalpic and entropic traps in the folding pathway of the substrate protein.
Significance
Hsp60/10 chaperonins are critical for cellular proteostasis in all kingdoms of life. In this study, we present that Hsp60/10 across different species have differences in the cavity properties and correlatively in their capability to remove entropic traps in folding pathways of GroEL/ES substrates; this is affected majorly by differences in the negative-charge density inside the chaperonin cavity. This dissimilarity leads to a remarkable difference between Hsp60/10 homologs in buffering mutational variations. However, most of them can remove nonnative contacts during folding of their substrates and alter the way the polypeptide chain undergoes hydrophobic collapse. We show that these homologs may have evolved specific modes of folding assistance by modulating cavity properties according to the requirements of their substrates.
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