TY - JOUR
T1 - The anti-sigma factor RsrA responds to oxidative stress by reburying its hydrophobic core
AU - Rajasekar, Karthik V.
AU - Zdanowski, Konrad
AU - Yan, Jun
AU - Hopper, Jonathan T.S.
AU - Francis, Marie-Louise R.
AU - Seepersad, Colin
AU - Sharp, Connor
AU - Pecqueur, Ludovic
AU - Werner, Jorn M.
AU - Robinson, Carol V.
AU - Mohammed, Shabaz
AU - Potts, Jennifer Robyn
AU - Kleanthous, Colin
N1 - © The Author(s) 2016
PY - 2016/7/19
Y1 - 2016/7/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84979010648&partnerID=8YFLogxK
U2 - 10.1038/ncomms12194
DO - 10.1038/ncomms12194
M3 - Article
SN - 2041-1723
VL - 7
JO - Nature Communications
JF - Nature Communications
M1 - 12194
ER -