ArticleProtein science : a publication of the Protein Society2022
Coevolution-derived native and non-native contacts determine the emergence of a novel fold in a universally conserved family of transcription factors.
Article in Protein science : a publication of the Protein Society, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 15 citations in OpenAlex.
- Fold-Switching Proteins.Annual review of biophysics · 2026Review
- Exploration of the structural and functional diversity in the metamorphic RfaH subfamily.bioRxiv : the preprint server for biology · 2026Article
- Mapping the energy landscape of a fold-switching protein MAD2.Protein science : a publication of the Protein Society · 2025Article
- Fold-switching proteins.ArXiv · 2025Article
- Large-scale predictions of alternative protein conformations by AlphaFold2-based sequence association.Nature communications · 2025Article
- Proteins with alternative folds reveal blind spots in AlphaFold-based protein structure prediction.Current opinion in structural biology · 2025Review
- Proteins with alternative folds reveal blind spots in AlphaFold-based protein structure prediction.ArXiv · 2024Article
- AlphaFold predictions of fold-switched conformations are driven by structure memorization.Nature communications · 2024Article
- Metamorphic proteins and how to find them.Current opinion in structural biology · 2024Review
- Residue coevolution and mutational landscape for OmpR and NarL response regulator subfamilies.Biophysical journal · 2024Article
- Article
- Evolutionary selection of proteins with two folds.Nature communications · 2023Article
- Fluid protein fold space and its implications.BioEssays : news and reviews in molecular, cellular and developmental biology · 2023Article
- Coevolution and smFRET Enhances Conformation Sampling and FRET Experimental Design in Tandem PDZ1-2 Proteins.The journal of physical chemistry. B · 2023Article
- Evolutionary selection of proteins with two folds.bioRxiv : the preprint server for biology · 2023Article
- Coevolution-derived native and non-native contacts determine the emergence of a novel fold in a universally conserved family of transcription factors.Protein science : a publication of the Protein Society · 2022Article
- Metamorphic proteins under a computational microscope: Lessons from a fold-switching RfaH protein.Computational and structural biotechnology journal · 2022Review
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Authors and funding
3 authors at 2 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
Abstract
The NusG protein family is structurally and functionally conserved in all domains of life. Its members directly bind RNA polymerases and regulate transcription processivity and termination. RfaH, a divergent sub-family in its evolutionary history, is known for displaying distinct features than those in NusG proteins, which allows them to regulate the expression of virulence factors in enterobacteria in a DNA sequence-dependent manner. A striking feature is its structural interconversion between an active fold, which is the canonical NusG three-dimensional structure, and an autoinhibited fold, which is distinctively novel. How this novel fold is encoded within RfaH sequence to encode a metamorphic protein remains elusive. In this work, we used publicly available genomic RfaH protein sequences to construct a complete multiple sequence alignment, which was further augmented with metagenomic sequences and curated by predicting their secondary structure propensities using JPred. Coevolving pairs of residues were calculated from these sequences using plmDCA and GREMLIN, which allowed us to detect the enrichment of key metamorphic contacts after sequence filtering. Finally, we combined our coevolutionary predictions with molecular dynamics to demonstrate that these interactions are sufficient to predict the structures of both native folds, where coevolutionary-derived non-native contacts may play a key role in achieving the compact RfaH novel fold. All in all, emergent coevolutionary signals found within RfaH sequences encode the autoinhibited and active folds of this protein, shedding light on the key interactions responsible for the action of this metamorphic protein.
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