Identification of a covert evolutionary pathway between two protein folds

Devlina Chakravarty, Shwetha Sreenivasan, Liskin Swint-Kruse and Lauren L. Porter ()
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Devlina Chakravarty: National Institutes of Health
Shwetha Sreenivasan: The University of Kansas Medical Center
Liskin Swint-Kruse: The University of Kansas Medical Center
Lauren L. Porter: National Institutes of Health

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Although homologous protein sequences are expected to adopt similar structures, some amino acid substitutions can interconvert α-helices and β-sheets. Such fold switching may have occurred over evolutionary history, but supporting evidence has been limited by the: (1) abundance and diversity of sequenced genes, (2) quantity of experimentally determined protein structures, and (3) assumptions underlying the statistical methods used to infer homology. Here, we overcome these barriers by applying multiple statistical methods to a family of ~600,000 bacterial response regulator proteins. We find that their homologous DNA-binding subunits assume divergent structures: helix-turn-helix versus α-helix + β-sheet (winged helix). Phylogenetic analyses, ancestral sequence reconstruction, and AlphaFold2 models indicate that amino acid substitutions facilitated a switch from helix-turn-helix into winged helix. This structural transformation likely expanded DNA-binding specificity. Our approach uncovers an evolutionary pathway between two protein folds and provides a methodology to identify secondary structure switching in other protein families.

Date: 2023
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DOI: 10.1038/s41467-023-38519-0

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