Identification of a Molecular Latch that Regulates Staphylococcal Virulence

Qian Xie, Aishan Zhao, Philip D. Jeffrey, Minyoung Kevin Kim, Bonnie Lynn Bassler, Howard A. Stone, Richard P. Novick, Thomas William Muir

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Virulence induction in the Staphylococcus aureus is under the control of a quorum sensing (QS) circuit encoded by the accessory gene regulator (agr) locus. Allelic variation within agr produces four QS specificity groups, each producing a unique secreted autoinducer peptide (AIP) and receptor histidine kinase (RHK), AgrC. Cognate AIP-AgrC interactions activate virulence through a two-component signaling cascade, whereas non-cognate pairs are generally inhibitory. Here we pinpoint a key hydrogen-bonding interaction within AgrC that acts as a switch to convert helical motions propagating from the receptor sensor domain into changes in inter-domain association within the kinase module. AgrC mutants lacking this interaction are constitutively active in vitro and in vivo, the latter leading to a pronounced attenuation of S. aureus biofilm formation. Thus, our work sheds light on the regulation of this biomedically important RHK.

Original languageEnglish (US)
Pages (from-to)548-558.e4
JournalCell Chemical Biology
Volume26
Issue number4
DOIs
StatePublished - Apr 18 2019

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Keywords

  • Staphylococcus aureus
  • agr interference
  • allosteric regulation
  • autoinducing peptides
  • biofilm formation
  • conformational equilibrium
  • constitutive mutations
  • docking interaction
  • protein histidine kinase AgrC
  • quorum sensing

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