ArticleBiophysical journal2020
Differential Local Stability Governs the Metamorphic Fold Switch of Bacterial Virulence Factor RfaH.
Article in Biophysical journal, 2020. 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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Who cites it
17 citing papers in PubMed, 32 citations in OpenAlex.
- Embrace Disorder as a Function: Bio-Informed Biomaterials Design Advanced by Intrinsically Disordered Proteins.Biomimetics (Basel, Switzerland) · 2026Article
- Computational and experimental assessment of key interdomain residues controlling the fold-switch of RfaH.Protein science : a publication of the Protein Society · 2025Article
- Statistical Thermodynamics of the Protein Ensemble: Mediating Function and Evolution.Annual review of biophysics · 2025Review
- A contact-based analysis of local energetic frustration dynamics identifies key residues enabling RfaH fold-switch.Protein science : a publication of the Protein Society · 2024Article
- An integrative approach to protein sequence design through multiobjective optimization.PLoS computational biology · 2024Article
- Metamorphic proteins and how to find them.Current opinion in structural biology · 2024Review
- Concerted transformation of a hyper-paused transcription complex and its reinforcing protein.Nature communications · 2024Article
- An integrative approach to protein sequence design through multiobjective optimization.bioRxiv : the preprint server for biology · 2024Article
- Exploring the structural acrobatics of fold-switching proteins using simplified structure-based models.Biophysical reviews · 2023Review
- DNA facilitates heterodimerization between human transcription factors FoxP1 and FoxP2 by increasing their conformational flexibility.iScience · 2023Article
- Creative destruction: New protein folds from old.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Article
- 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
- Dimer dissociation is a key energetic event in the fold-switch pathway of KaiB.Biophysical journal · 2022Article
- Metamorphic proteins under a computational microscope: Lessons from a fold-switching RfaH protein.Computational and structural biotechnology journal · 2022Review
- The N-terminal domain of RfaH plays an active role in protein fold-switching.PLoS computational biology · 2021Article
- NusG, an Ancient Yet Rapidly Evolving Transcription Factor.Frontiers in microbiology · 2020Review
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Authors and funding
7 authors at 4 institutions in 3 countries.
Funding
Abstract
RfaH, a two-domain protein from a universally conserved NusG/Spt5 family of regulators, is required for the transcription and translation of long virulence and conjugation operons in many Gram-negative bacterial pathogens. Escherichia coli RfaH action is controlled by a unique large-scale structural rearrangement triggered by recruitment to transcription elongation complexes through a specific DNA element. Upon recruitment, the C-terminal domain of RfaH refolds from an α-hairpin, which is bound to RNA polymerase binding site within the N-terminal domain, into an unbound β-barrel that interacts with the ribosome. Although structures of the autoinhibited (α-hairpin) and active (β-barrel) states and plausible refolding pathways have been reported, how this reversible switch is encoded within RfaH sequence and structure is poorly understood. Here, we combined hydrogen-deuterium exchange measurements by mass spectrometry and nuclear magnetic resonance with molecular dynamics to evaluate the differential local stability between both RfaH folds. Deuteron incorporation reveals that the tip of the C-terminal hairpin (residues 125-145) is stably folded in the autoinhibited state (∼20% deuteron incorporation), whereas the rest of this domain is highly flexible (>40% deuteron incorporation), and its flexibility only decreases in the β-folded state. Computationally predicted ΔG agree with these results by displaying similar anisotropic stability within the tip of the α-hairpin and on neighboring N-terminal domain residues. Remarkably, the β-folded state shows comparable structural flexibility than nonmetamorphic homologs. Our findings provide information critical for understanding the metamorphic behavior of RfaH and other chameleon proteins and for devising targeted strategies to combat bacterial infections.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.