title: Structural Insights into Streptococcal Competence Regulation by the Cell-to-Cell Communication System ComRS.
abstract: In Gram-positive bacteria, cell-to-cell communication mainly relies on extracellular signaling peptides, which elicit a response either indirectly, by triggering a two-component phosphorelay, or directly, by binding to cytoplasmic effectors. The latter comprise the RNPP family (Rgg and original regulators Rap, NprR, PrgX and PlcR), whose members regulate important bacterial processes such as sporulation, conjugation, and virulence. RNPP proteins are increasingly considered as interesting targets for the development of new antibacterial agents. These proteins are characterized by a TPR-type peptide-binding domain, and except for Rap proteins, also contain an N-terminal HTH-type DNA-binding domain and display a transcriptional activity. Here, we elucidate the structure-function relationship of the transcription factor ComR, a new member of the RNPP family, which positively controls competence for natural DNA transformation in streptococci. ComR is directly activated by the binding of its associated pheromone XIP, the mature form of the comX/sigX-inducing-peptide ComS. The crystal structure analysis of ComR from Streptococcus thermophilus combined with a mutational analysis and in vivo assays allows us to propose an original molecular mechanism of the ComR regulation mode. XIP-binding induces release of the sequestered HTH domain and ComR dimerization to allow DNA binding. Importantly, we bring evidence that this activation mechanism is conserved and specific to ComR orthologues, demonstrating that ComR is not an Rgg protein as initially proposed, but instead constitutes a new member of the RNPP family. In addition, identification of XIP and ComR residues important for competence activation constitutes a crucial step towards the design of antagonistic strategies to control gene exchanges among streptococci.
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette cedex, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Talagas
authors.affiliation: Institute of Life Sciences (ISV), Biochemistry, Biophysics and Genetics of Microorganisms (BBGM), Université catholique de Louvain, Croix du Sud, 4-5 (L7.07.06), Louvain-La-Neuve, Belgium.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Fontaine
authors.affiliation: Institute of Life Sciences (ISV), Biochemistry, Biophysics and Genetics of Microorganisms (BBGM), Université catholique de Louvain, Croix du Sud, 4-5 (L7.07.06), Louvain-La-Neuve, Belgium.
authors.forename: Laura
authors.initials: L
authors.lastname: Ledesma-García
authors.affiliation: Institute of Life Sciences (ISV), Biochemistry, Biophysics and Genetics of Microorganisms (BBGM), Université catholique de Louvain, Croix du Sud, 4-5 (L7.07.06), Louvain-La-Neuve, Belgium.
authors.forename: Johann
authors.identifier: 0000-0002-3721-4307
authors.initials: J
authors.lastname: Mignolet
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette cedex, France.
authors.forename: Inès
authors.identifier: 0000-0003-2770-7439
authors.initials: I
authors.lastname: Li de la Sierra-Gallay
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette cedex, France.
authors.forename: Noureddine
authors.initials: N
authors.lastname: Lazar
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette cedex, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Aumont-Nicaise
authors.affiliation: Dept. of Medicinal Chemistry and Pharmacognosy, Center for Biomolecular Sciences, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Federle
authors.affiliation: Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, Illinois, United States of America.|Center for Structural Biology, Research Resources Center, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Gerd
authors.initials: G
authors.lastname: Prehna
authors.affiliation: Institute of Life Sciences (ISV), Biochemistry, Biophysics and Genetics of Microorganisms (BBGM), Université catholique de Louvain, Croix du Sud, 4-5 (L7.07.06), Louvain-La-Neuve, Belgium.
authors.forename: Pascal
authors.initials: P
authors.lastname: Hols
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette cedex, France.
authors.forename: Sylvie
authors.identifier: 0000-0003-4973-9941
authors.initials: S
authors.lastname: Nessler
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology; D018360:Crystallography, X-Ray; D061269:DNA Transformation Competence; D024202:Electrophoretic Mobility Shift Assay; D015964:Gene Expression Regulation, Bacterial; D010675:Pheromones / Q000378:metabolism; D053038:Quorum Sensing / Q000502:physiology*; D048249:Streptococcus thermophilus / Q000502:physiology*
chemical_list: D001426:Bacterial Proteins; D010675:Pheromones