Identification of a covert evolutionary pathway between two protein folds
Open accessPublished version of a preprint
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.
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AlphaMut: A Deep Reinforcement Learning Model to Suggest Helix-Disrupting Mutations
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- Authors
- Chakravarty, D., Sreenivasan, S., Swint-Kruse, L., & Porter, L. L.
- Affiliations
- National Institutes of Health (US)
- University of Kansas Medical Center (US)
- Corresponding author
- Porter, Lauren L.
- Venue
- Nature Communications
- Published
- 2023-06-01
- Volume
- 14
- Issue
- 1
- Pages
- 3177-3177
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC10235069
- OpenAlex
- W4379054654
- Cited by
- 29
- References
- 8
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 8 · 2023: 6
- FWCI
- 2.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine (ZIA 202011-04)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- protein fold evolution, fold switching, helix-turn-helix, DNA-binding proteins, ancestral sequence reconstruction, homology inference, DNA binding specificity, AlphaFold2
- MeSH terms
- Bacterial Proteins, DNA, DNA-Binding Proteins, Phylogeny, Sequence Alignment, Sequence Homology, Amino Acid
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