Evolutionary selection of proteins with two folds

Schafer, J. W.; Porter, L.

doi:10.1101/2023.01.18.524637

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bioRxiv · 10.1101/2023.01.18.524637

Evolutionary selection of proteins with two folds

Schafer, J. W.·Porter, L.

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Abstract

Although most globular proteins fold into a single stable structure1, an increasing number have been shown to remodel their secondary and tertiary structures in response to cellular stimuli2. State-of-the-art algorithms3-5 predict that these fold-switching proteins assume only one stable structure6,7, missing their functionally critical alternative folds. Why these algorithms predict a single fold is unclear, but all of them infer protein structure from coevolved amino acid pairs. Here, we hypothesize that coevolutionary signatures are being missed. Suspecting that over-represented single-fold sequences may be masking these signatures, we developed an approach to search both highly diverse protein superfamilies-composed of single-fold and fold-switching variants-and protein subfamilies with more fold-switching variants. This approach successfully revealed coevolution of amino acid pairs uniquely corresponding to both conformations of 56/58 fold-switching proteins from distinct families. Then, using a set of coevolved amino acid pairs predicted by our approach, we successfully biased AlphaFold25 to predict two experimentally consistent conformations of a candidate protein with unsolved structure. The discovery of widespread dual-fold coevolution indicates that fold-switching sequences have been preserved by natural selection, implying that their functionalities provide evolutionary advantage and paving the way for predictions of diverse protein structures from single sequences.

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Schafer, J. W., Porter, L.. 2023-01-20. Evolutionary selection of proteins with two folds. https://doi.org/10.1101/2023.01.18.524637

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