title: Periplasmic domain of the sensor-kinase BvgS reveals a new paradigm for the Venus flytrap mechanism.
abstract: Two-component sensory transduction systems control important bacterial programs. In Bordetella pertussis, expression of the virulence regulon is controlled by the unorthodox BvgAS two-component system. BvgS is the prototype of a family of sensor-kinases that harbor periplasmic domains homologous to bacterial solute-binding proteins. Although BvgAS is active under laboratory conditions, no activating signal has been identified, only negative modulators. Here we show that the second periplasmic domain of BvgS interacts with modulators and adopts a Venus flytrap (VFT) fold. X-ray crystallography reveals that the two lobes of VFT2 delimitate a ligand-binding cavity enclosing fortuitous ligands. Most substitutions of putative ligand-binding residues in the VFT2 cavity keep BvgS active, and alteration of the cavity's electrostatic potential affects responsiveness to modulation. The crystal structure of this VFT2 variant conferring constitutive kinase activity to BvgS shows a closed cavity with another nonspecific ligand. Thus, VFT2 is closed and active without a specific agonist ligand, in contrast to typical VFTs. Modulators are antagonists of VFT2 that interrupt signaling. BvgAS is active for most of the B. pertussis infectious cycle, consistent with the proposed mechanism.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Center for Infection and Immunity of Lille, F-59019 Lille, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Herrou
authors.forename: Coralie
authors.initials: C
authors.lastname: Bompard
authors.forename: René
authors.initials: R
authors.lastname: Wintjens
authors.forename: Elian
authors.initials: E
authors.lastname: Dupré
authors.forename: Eve
authors.initials: E
authors.lastname: Willery
authors.forename: Vincent
authors.initials: V
authors.lastname: Villeret
authors.forename: Camille
authors.initials: C
authors.lastname: Locht
authors.forename: Rudy
authors.initials: R
authors.lastname: Antoine
authors.forename: Françoise
authors.initials: F
authors.lastname: Jacob-Dubuisson
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001886:Bordetella pertussis / Q000378:metabolism* / Q000472:pathogenicity; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019897:Periplasm / Q000201:enzymology*; D011489:Protein Denaturation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D014157:Transcription Factors; C080662:bvgS protein, Bordetella pertussis