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Updated: Jul 28, 2025
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Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues
Published on: July 14, 2015
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Identification of a covert evolutionary pathway between two protein folds
Devlina Chakravarty1, Shwetha Sreenivasan2, Liskin Swint-Kruse2
1National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, 20894, USA.
Nature Communications
|June 1, 2023
Summary
Protein structure can change due to amino acid substitutions, enabling evolutionary adaptation. This study reveals a switch from helix-turn-helix to winged helix folds in bacterial proteins, expanding DNA-binding capabilities.
Area of Science:
- Protein structure and evolution
- Bioinformatics and computational biology
- Molecular evolution
Background:
- Homologous proteins typically share similar structures, but exceptions exist.
- Amino acid substitutions can drive interconversion between secondary structures like alpha-helices and beta-sheets.
- Evidence for evolutionary protein fold switching has been historically limited.
Purpose of the Study:
- To investigate the evolutionary pathway of protein fold switching.
- To identify instances of structural transformation in homologous protein families.
- To explore how structural changes impact protein function, specifically DNA-binding specificity.
Main Methods:
- Analysis of ~600,000 bacterial response regulator proteins.
- Application of multiple statistical methods for homology inference.
- Phylogenetic analysis, ancestral sequence reconstruction, and AlphaFold2 modeling.
Main Results:
- Identified homologous DNA-binding subunits with divergent structures: helix-turn-helix and winged helix (alpha-helix + beta-sheet).
- Demonstrated that amino acid substitutions drove the evolutionary switch from helix-turn-helix to winged helix.
- Showcased AlphaFold2's utility in predicting structures for evolutionary studies.
Conclusions:
- Protein fold switching is an evolutionary mechanism that can occur via amino acid substitutions.
- The transition from helix-turn-helix to winged helix likely enhanced DNA-binding specificity.
- Developed a novel methodology for identifying secondary structure switching in protein families.
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