Symmetric signalling within asymmetric dimers of the Staphylococcus aureus receptor histidine kinase AgrC

Laboratory of Synthetic Protein Chemistry, Training Program in Chemical Biology, The Rockefeller University, New York, NY 10065, USA.
Molecular Microbiology (Impact Factor: 4.42). 09/2009; 74(1):44-57. DOI: 10.1111/j.1365-2958.2009.06849.x
Source: PubMed


Virulence in Staphylococcus aureus is largely under control of the accessory gene regulator (agr) quorum-sensing system. The AgrC receptor histidine kinase detects its autoinducing peptide (AIP) ligand and generates an intracellular signal resulting in secretion of virulence factors. Although agr is a well-studied quorum-sensing system, little is known about the mechanism of AgrC activation. By co-immunoprecipitation analysis and intermolecular complementation of receptor mutants, we showed that AgrC forms ligand-independent dimers that undergo trans-autophosphorylation upon interaction with AIP. Remarkably, addition of specific AIPs to AgrC mutant dimers with only one functional sensor domain caused symmetric activation of either kinase domain despite the sensor asymmetry. Furthermore, mutant dimers involving one constitutive protomer demonstrated ligand-independent activity, irrespective of which protomer was kinase deficient. These results demonstrate that signalling through either individual AgrC protomer causes symmetric activation of both kinase domains. We suggest that such signalling across the dimer interface may be an important mechanism for dimeric quorum-sensing receptors to rapidly elicit a response upon signal detection.

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    • "AgrC, a member of the HPK10 family, is a membrane protein that is important in signal transduction. Although AgrC has been extensively studied [6], [17]–[21], [38]–[41], biochemical and biophysical studies of AgrC in vitro are challenging because of its amphipathic nature and the difficulty of expressing native protein in large amounts. Therefore, in this present study, a truncated AgrCTM5-6C containing the last two transmembrane segments and cytoplasmic domain was constructed and overproduced and purified from an E. coli system (Fig.1). "
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