Identification of a Molecular Latch that Regulates Staphylococcal Virulence.

TitleIdentification of a Molecular Latch that Regulates Staphylococcal Virulence.
Publication TypeJournal Article
Year of Publication2019
AuthorsXie, Q, Zhao, A, Jeffrey, PD, Kim, MKevin, Bassler, BL, Stone, HA, Novick, RP, Muir, TW
JournalCell Chem Biol
Volume26
Issue4
Pagination548-558.e4
Date Published2019 04 18
ISSN2451-9448
KeywordsAllosteric Regulation, Bacterial Proteins, Humans, Hydrogen Bonding, Molecular Docking Simulation, Peptides, Cyclic, Protein Conformation, Protein Kinases, Quorum Sensing, Signal Transduction, Staphylococcal Infections, Staphylococcus aureus, Virulence
Abstract

<p>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.</p>

DOI10.1016/j.chembiol.2019.01.006
Alternate JournalCell Chem Biol
PubMed ID30773482
PubMed Central IDPMC6506218
Grant ListP41 GM103485 / GM / NIGMS NIH HHS / United States
R01 AI042783 / AI / NIAID NIH HHS / United States
R01 GM095880 / GM / NIGMS NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States