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Wu, Hao; Liu, Qiang; Casas-Pastor, Delia; Duerr, Franziska; Mascher, Thorsten; Fritz, Georg (2019): The role of C-terminal extensions in controlling ECF sigma factor activity in the widely conserved groups ECF41 and ECF42. In: Molecular Microbiology, Vol. 112, No. 2: pp. 498-514
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The activity of extracytoplasmic function sigma-factors (ECFs) is typically regulated by anti-sigma factors. In a number of highly abundant ECF groups, including ECF41 and ECF42, sigma-factors contain fused C-terminal protein domains, which provide the necessary regulatory function instead. Here, we identified the contact interface between the C-terminal extension and the core sigma-factor regions required for controlling ECF activity. We applied direct coupling analysis (DCA) to infer evolutionary covariation between contacting amino acid residues for groups ECF41 and ECF42. Mapping the predicted interactions to a recently solved ECF41 structure demonstrated that DCA faithfully identified an important contact interface between the SnoaL-like extension and the linker between the sigma(2) and sigma(4) domains. Systematic alanine substitutions of contacting residues support this model and suggest that this interface stabilizes a compact conformation of ECF41 with low transcriptional activity. For group ECF42, DCA supports a structural homology model for their C-terminal tetratricopeptide repeat (TPR) domains and predicts an intimate contact between the first TPR-helix and the sigma(4) domain. Mutational analyses demonstrate the essentiality of the predicted interactions for ECF42 activity. These results indicate that C-terminal extensions indeed bind and regulate the core ECF regions, illustrating the potential of DCA for discovering regulatory motifs in the ECF subfamily.