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Cell Chem Biol. 2019 Apr 18;26(4):548-558.e4. doi: 10.1016/j.chembiol.2019.01.006. Epub 2019 Feb 14.

Identification of a Molecular Latch that Regulates Staphylococcal Virulence.

Author information

1
Department of Chemistry, Princeton University, Frick Chemistry Laboratory, Washington Road, Princeton, NJ 08544-0015, USA.
2
Department of Molecular Biology, Princeton University, Schultz Laboratory, Washington Road, Princeton, NJ 08544, USA.
3
Department of Molecular Biology, Princeton University, Schultz Laboratory, Washington Road, Princeton, NJ 08544, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
4
Department of Mechanical and Aerospace Engineering, Princeton University, Engineering Quadrangle, Olden Street, Princeton, NJ 08544, USA.
5
Skirball Institute, Department of Microbiology, NYU Medical Center, 540-562 First Avenue, New York, NY 10016, USA.
6
Department of Chemistry, Princeton University, Frick Chemistry Laboratory, Washington Road, Princeton, NJ 08544-0015, USA. Electronic address: muir@princeton.edu.

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.

KEYWORDS:

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

PMID:
30773482
PMCID:
PMC6506218
[Available on 2020-04-18]
DOI:
10.1016/j.chembiol.2019.01.006

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