Reversible fold-switching controls the functional cycle of the antitermination factor RfaH
By P. Zuber, K. Schweimer, P. Rösch, I. Artsimovitch, S. Knauer. 2019
58 citations recorded by the source corpus.
RfaH, member of the NusG/Spt5 family, activates virulence genes in Gram-negative pathogens. RfaH exists in two states, with its C-terminal domain (CTD) folded either as α-helical hairpin or β-barrel. In free RfaH, the α-helical CTD interacts with, and masks the RNA polymerase binding site on, the N-terminal domain, autoinhibiting RfaH and restricting its recruitment to opsDNA sequences. Upon activation, the domains separate and the CTD refolds into the β-barrel, which recruits a ribosome, activating translation. Using NMR spectroscopy, we show that only a complete ops-paused transcription elongation complex activates RfaH, probably via a transient encounter complex, allowing the refolded CTD to bind ribosomal protein S10. We also demonstrate that upon release from the elongation complex, the CTD transforms back into the autoinhibitory α-state, resetting the cycle. Transformation-coupled autoinhibition allows RfaH to achieve high specificity and potent activation of gene expression. The antitermination factor RfaH adopts two functional states where its C-terminal domain is folded either as an α-helical hairpin or β-barrel. Here the authors employ solution state NMR measurements to show that the C-terminal domain transforms into the β-barrel only upon binding to the elongation complex and refolds back after dissociation.
Subfields: Genetics, Molecular Biology
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In Genetics
In Molecular Biology
- Lucy J. Colwell
- Sergey Ovchinnikov
- Dorothee Kern
- Hannah K. Wayment-Steele
- César A. Ramírez-Sarmiento
- Pablo Galaz-Davison
- Diego U. Ferreiro
- Anne-Florence Bitbol
Citations in the corpus
- Predicting multiple conformations via sequence clustering and AlphaFold2 (2023, neutral): “In RfaH, the C-terminal domain (CTD) interconverts between an α-helix bundle and a β-barrel through binding to functional partners 23 .”
- Coevolution‐derived native and non‐native contacts determine the emergence of a novel fold in a universally conserved family of transcription factors (2022, background): “Computational approaches have sought to determine the fold-switching mechanism of this protein,9–15 and experimental structural work has been performed to characterize its binding to the TEC.(6,16) Recent reports suggest that during evolution, protein metamorphosis emerges as the connecting path bet”
- Prediction of multiple conformational states by combining sequence clustering with AlphaFold2 (2022, background): “In the active state, the CTD unbinds and forms the β -barrel ( Figure 4A ) 9,10 .”