Activation and inhibition of the receptor histidine kinase AgrC occurs through opposite helical transduction motions

Boyuan Wang, Aishan Zhao, Richard P. Novick, Tom W. Muir

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Staphylococcus aureus virulence is regulated when secreted autoinducing peptides (AIPs) are recognized by a membrane-bound receptor histidine kinase (RHK), AgrC. Some AIPs are agonists of virulence gene expression, while others are antagonists. It is unclear how AIP binding regulates AgrC activity. Here, we reconstitute an AgrC family member, AgrC-I, using nanometer-scale lipid bilayer discs. We show that AgrC-I requires membranes rich in anionic lipids to function. The agonist, AIP-I, binds AgrC-I noncooperatively in a 2:2 stoichiometry, while an antagonist ligand, AIP-II, functions as an inverse agonist of the kinase activity. We also demonstrate the kinase and sensor domains in AgrC are connected by a helical linker whose conformational state exercises rheostat-like control over the kinase activity. Binding of agonist or inverse-agonist peptides results in twisting of the linker in different directions. These two observations provide a view of the molecular motions triggered by ligand binding in an intact membrane-bound RHK.

Original languageEnglish (US)
Pages (from-to)929-940
Number of pages12
JournalMolecular Cell
Volume53
Issue number6
DOIs
StatePublished - Mar 20 2014

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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