The anti-sigma factor RsrA responds to oxidative stress by reburying its hydrophobic core

Karthik V. Rajasekar, Konrad Zdanowski, Jun Yan, Jonathan T.S. Hopper, Marie-Louise R. Francis, Colin Seepersad, Connor Sharp, Ludovic Pecqueur, Jorn M. Werner, Carol V. Robinson, Shabaz Mohammed, Jennifer Robyn Potts, Colin Kleanthous

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Redox-regulated effector systems that counteract oxidative stress are essential for all forms of life. Here we uncover a new paradigm for sensing oxidative stress centred on the hydrophobic core of a sensor protein. RsrA is an archetypal zinc-binding anti-sigma factor that responds to disulfide stress in the cytoplasm of Actinobacteria. We show that RsrA utilizes its hydrophobic core to bind the sigma factor σ R preventing its association with RNA polymerase, and that zinc plays a central role in maintaining this high-affinity complex. Oxidation of RsrA is limited by the rate of zinc release, which weakens the RsrA-σ R complex by accelerating its dissociation. The subsequent trigger disulfide, formed between specific combinations of RsrA's three zinc-binding cysteines, precipitates structural collapse to a compact state where all σ R-binding residues are sequestered back into its hydrophobic core, releasing σ R to activate transcription of anti-oxidant genes.

Original languageEnglish
Article number12194
Number of pages14
JournalNature Communications
Publication statusPublished - 19 Jul 2016

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