Faculty Collaboration Database

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. PLoS Pathog 2018 May;14(5):e1007052

Date

05/12/2018

Pubmed ID

29750817

Pubmed Central ID

PMC5965902

DOI

10.1371/journal.ppat.1007052

Scopus ID

2-s2.0-85047976604 (requires institutional sign-in at Scopus site)   21 Citations

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.

Author List

Glanville DG, Han L, Maule AF, Woodacre A, Thanki D, Abdullah IT, Morrissey JA, Clarke TB, Yesilkaya H, Silvaggi NR, Ulijasz AT

Author

Nicholas R. Silvaggi PhD Assistant Professor in the Chemistry and Biochemistry department at University of Wisconsin - Milwaukee

MESH terms used to index this publication - Major topics in bold

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