Many dissimilar protein domains switch between α-helix and β-sheet folds

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Nature Communications. 2022 Jul01;13(1). doi: 10.1101/2021.06.10.447921

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Many dissimilar protein domains switch between α-helix and β-sheet folds Looger Lab

Porter Lauren, Kim Allen, Rimal Swechha, Looger Loren, Majumdar Ananya, Mensh Brett, Starich Mary

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Abstract

Hundreds 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.

PMID: 35778397 [PubMed - indexed for MEDLINE]

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bioRxiv PrePrint https://doi.org/10.1101/2021.06.10.447921

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Many dissimilar protein domains switch between α-helix and β-sheet folds

Abstract

PMID: 35778397 [PubMed - indexed for MEDLINE]

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