RitR is an archetype for a novel family of redox sensors in the streptococci that has evolved from two-component response regulators and is required for pneumococcal colonization

David G Glanville, Lanlan Han, Andrew F Maule, Alexandra Woodacre, Devsaagar Thanki, Iman Tajer Abdullah, Julie A Morrissey, Thomas B Clarke, Hasan Yesilkaya, Nicholas R Silvaggi, Andrew T Ulijasz

Research output: Contribution to JournalArticlepeer-review

Abstract

To survive diverse host environments, the human pathogen Streptococcus pneumoniae must prevent its self-produced, extremely high levels of peroxide from reacting with intracellular iron. However, the regulatory mechanism(s) by which the pneumococcus accomplishes this balance remains largely enigmatic, as this pathogen and other related streptococci lack all known redox-sensing transcription factors. Here we describe a two-component-derived response regulator, RitR, as the archetype for a novel family of redox sensors in a subset of streptococcal species. We show that RitR works to both repress iron transport and enable nasopharyngeal colonization through a mechanism that exploits a single cysteine (Cys128) redox switch located within its linker domain. Biochemical experiments and phylogenetics reveal that RitR has diverged from the canonical two-component virulence regulator CovR to instead dimerize and bind DNA only upon Cys128 oxidation in air-rich environments. Atomic structures show that Cys128 oxidation initiates a "helical unravelling" of the RitR linker region, suggesting a mechanism by which the DNA-binding domain is then released to interact with its cognate regulatory DNA. Expanded computational studies indicate this mechanism could be shared by many microbial species outside the streptococcus genus.

Original languageEnglish
Pages (from-to)1-41
Number of pages41
JournalPLoS pathogens
Volume14
Issue number5
DOIs
Publication statusPublished - 11 May 2018

Keywords

  • Bacterial Proteins/metabolism
  • Cysteine/metabolism
  • Gene Expression Regulation, Bacterial/genetics
  • Hydrogen Peroxide/metabolism
  • Ion Transport/physiology
  • Iron/metabolism
  • Oxidation-Reduction
  • Repressor Proteins/metabolism
  • Response Elements/physiology
  • Signal Transduction
  • Streptococcus pneumoniae/genetics
  • Streptococcus pyogenes/genetics
  • Transcription Factors/metabolism
  • Virulence/genetics

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