title: Adenylylation of Gyrase and Topo IV by FicT Toxins Disrupts Bacterial DNA Topology.
abstract: Toxin-antitoxin (TA) modules are ubiquitous molecular switches controlling bacterial growth via the release of toxins that inhibit cell proliferation. Most of these toxins interfere with protein translation, but a growing variety of other mechanisms hints at a diversity that is not yet fully appreciated. Here, we characterize a group of FIC domain proteins as toxins of the conserved and abundant FicTA family of TA modules, and we reveal that they act by suspending control of cellular DNA topology. We show that FicTs are enzymes that adenylylate DNA gyrase and topoisomerase IV, the essential bacterial type IIA topoisomerases, at their ATP-binding site. This modification inactivates both targets by blocking their ATPase activity, and, consequently, causes reversible growth arrest due to the knotting, catenation, and relaxation of cellular DNA. Our results give insight into the regulation of DNA topology and highlight the remarkable plasticity of FIC domain proteins.
authors: Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors: Alexander
authors: A
authors: Harms
authors: Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland; Focal Area Structural Biology and Biophysics, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors: Frédéric Valentin
authors: FV
authors: Stanger
authors: Centre for Cell and Molecular Biosciences, Newcastle University, NE2 4AX Newcastle upon Tyne, UK.
authors: Patrick Daniel
authors: PD
authors: Scheu
authors: Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors: Imke Greet
authors: IG
authors: de Jong
authors: Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland; Focal Area Structural Biology and Biophysics, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors: Arnaud
authors: A
authors: Goepfert
authors: Proteomics Core Facility, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors: Timo
authors: T
authors: Glatter
authors: Centre for Cell and Molecular Biosciences, Newcastle University, NE2 4AX Newcastle upon Tyne, UK; Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.
authors: Kenn
authors: K
authors: Gerdes
authors: Focal Area Structural Biology and Biophysics, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors: Tilman
authors: T
authors: Schirmer
authors: Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland. Electronic address: christoph.dehio@unibas.ch.
authors: Christoph
authors: C
authors: Dehio
mesh_terms: D001427:Bacterial Toxins / Q000378:metabolism*; D027081:DNA Gyrase / Q000378:metabolism*; D027101:DNA Topoisomerase IV / Q000378:metabolism*; D004269:DNA, Bacterial / Q000737:chemistry / Q000378:metabolism*; D004926:Escherichia coli / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D011550:Pseudomonas aeruginosa / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D004269:DNA, Bacterial; D029968:Escherichia coli Proteins; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase