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Although most globular proteins fold into a single stable structure 1 , an increasing number have been shown to remodel their secondary and tertiary structures in response to cellular stimuli 2 . State-of-the-art algorithms 3-5 predict that these fold-switching proteins assume only one stable structure 6,7 , 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 AlphaFold2 5 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.


Joseph W Schafer, Lauren L Porter. Evolutionary selection of proteins with two folds. bioRxiv : the preprint server for biology. 2023 Jan 20

PMID: 36789442

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