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1 Janelia Publications
Showing 1-1 of 1 resultsHundreds of millions of structured proteins sustain life through chemical interactions and catalytic reactions1. Though dynamic, these proteins are assumed to be built upon fixed scaffolds of secondary structure, α-helices and β-sheets. Experimentally determined structures of over >58,000 non-redundant proteins support this assumption, though it has recently been challenged by ∼100 fold-switching proteins2. These “metamorphic3” proteins, though ostensibly rare, raise the question of how many uncharacterized proteins have shapeshifting–rather than fixed–secondary structures. To address this question, we developed a comparative sequence-based approach that predicts fold-switching proteins from differences in secondary structure propensity. We applied this approach to the universally conserved NusG transcription factor family of ∼15,000 proteins, one of which has a 50-residue regulatory subunit experimentally shown to switch between α-helical and β-sheet folds4. Our approach predicted that 25% of the sequences in this family undergo similar α-helix ⇌ β-sheet transitions, a frequency two orders of magnitude larger than previously observed. Our predictions evade state-of-the-art computational methods but were confirmed experimentally by circular dichroism and nuclear magnetic resonance spectroscopy for all 10 assiduously chosen dissimilar variants. These results suggest that fold switching is a pervasive mechanism of transcriptional regulation in all kingdoms of life and imply that numerous uncharacterized proteins may also switch folds.