title: The anti-sigma factor RsrA responds to oxidative stress by reburying its hydrophobic core.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Karthik V
authors.initials: KV
authors.lastname: Rajasekar
authors.affiliation: Department of Biology, University of York, York YO10 5DD, UK.
authors.forename: Konrad
authors.initials: K
authors.lastname: Zdanowski
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Jonathan T S
authors.initials: JT
authors.lastname: Hopper
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Marie-Louise R
authors.initials: ML
authors.lastname: Francis
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Seepersad
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Connor
authors.initials: C
authors.lastname: Sharp
authors.affiliation: School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, UK.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Pecqueur
authors.affiliation: School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, UK.
authors.forename: Jörn M
authors.initials: JM
authors.lastname: Werner
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Carol V
authors.initials: CV
authors.lastname: Robinson
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.|Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Shabaz
authors.identifier: 0000-0003-2640-9560
authors.initials: S
authors.lastname: Mohammed
authors.affiliation: Department of Biology, University of York, York YO10 5DD, UK.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Potts
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Kleanthous
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D012808:Sigma Factor / Q000037:antagonists & inhibitors*; D015032:Zinc / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D012808:Sigma Factor; D015032:Zinc; D003545:Cysteine