title: Activation of the bacterial sensor kinase PhoQ by acidic pH.
abstract: The Salmonellae PhoQ sensor kinase senses the mammalian phagosome environment to activate a transcriptional program essential for virulence. The PhoQ periplasmic domain binds divalent cations, forming bridges with inner membrane phospholipids to maintain PhoQ repression. PhoQ also binds and is activated by cationic antimicrobial peptides. In this work, PhoQ is directly activated by exposure of the sensor domain to pH 5.5. NMR spectroscopy indicates that at acidic pH, the PhoQ periplasmic domain adopts a conformation different from that in the presence of divalent cations or antimicrobial peptides. The conformation is partially simulated by mutation of histidine 157, which is part of an interaction network that distinguishes the repressed conformation. The effects of antimicrobial peptides and pH on PhoQ activity are additive. We propose a model of activation by antimicrobial peptides via disruption of the cation bridges and/or by acidification of the periplasm through destabilization of the interaction network.
authors.affiliation: Department of Microbiology, University of Washington Medical School, Seattle, WA 98195, USA.
authors.forename: Lynne R
authors.initials: LR
authors.lastname: Prost
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Daley
authors.forename: Valerie
authors.initials: V
authors.lastname: Le Sage
authors.forename: Martin W
authors.initials: MW
authors.lastname: Bader
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Moual
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Klevit
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Miller
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002413:Cations, Divalent / Q000378:metabolism / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006639:Histidine / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008264:Macrophages / Q000201:enzymology / Q000382:microbiology; D008274:Magnesium / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D017434:Protein Structure, Tertiary; D012475:Salmonella / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D014774:Virulence
chemical_list: D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D002413:Cations, Divalent; C079792:PhoQ protein, Bacteria; D006639:Histidine; D008274:Magnesium