Anfinsen’s thermodynamic hypothesis postulates that protein structure is encoded in primary sequence, allowing macromolecules to reliably navigate to their native fold by minimizing their Gibb’s free energy. However, thermodynamic considerations alone are insufficient to govern in vivo protein self-assembly; some proteins form aggregates and misfold following denaturation, suggesting that kinetics play a significant role in assembly. Proteins in thermophilic species can maintain their structures and functions in extreme temperatures. However, it is unknown whether this phenomenon is a consequence of high thermodynamic stability of native states or high kinetic barriers blocking egress from native states attained during translation. In this study, limited proteolysis mass spectrometry is used to interrogate the refoldability of two closely related extremophilic proteomes: Thermus thermophilus, an obligate thermophile with an optimal growth temperature (OGT) of 70C, and Deinococcus radiodurans, a facultative extremophile resistant to extreme shocks (desiccation, acid, heat, vacuum, radiation, etc) with an OGT of 30C. The T. thermophilus proteome demonstrates high nonrefoldability, suggesting protein thermostability is a consequence of pervasive kinetic trapping of native states. In contrast, the D. radiodurans proteome appears highly refoldable, suggesting the ability for proteins to return to thermodynamically favorable native structures after severe environmental shocks was adaptive for this species.

Extremophilic proteome refoldability studies reveal distinct biophysical strategies to protect protein structure in vivo

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