title: Allostery and intrinsic disorder mediate transcription regulation by conditional cooperativity.
abstract: Regulation of the phd/doc toxin-antitoxin operon involves the toxin Doc as co- or derepressor depending on the ratio between Phd and Doc, a phenomenon known as conditional cooperativity. The mechanism underlying this observed behavior is not understood. Here we show that monomeric Doc engages two Phd dimers on two unrelated binding sites. The binding of Doc to the intrinsically disordered C-terminal domain of Phd structures its N-terminal DNA-binding domain, illustrating allosteric coupling between highly disordered and highly unstable domains. This allosteric effect also couples Doc neutralization to the conditional regulation of transcription. In this way, higher levels of Doc tighten repression up to a point where the accumulation of toxin triggers the production of Phd to counteract its action. Our experiments provide the basis for understanding the mechanism of conditional cooperative regulation of transcription typical of toxin-antitoxin modules. This model may be applicable for the regulation of other biological systems.
authors.affiliation: Structural Biology Brussels, Vrije Universiteit Brussels, Pleinlaan 2, B-1050 Brussels, Belgium. agarciap@vub.ac.be
authors.forename: Abel
authors.initials: A
authors.lastname: Garcia-Pino
authors.forename: Sreeram
authors.initials: S
authors.lastname: Balasubramanian
authors.forename: Lode
authors.initials: L
authors.lastname: Wyns
authors.forename: Ehud
authors.initials: E
authors.lastname: Gazit
authors.forename: Henri
authors.initials: H
authors.lastname: De Greve
authors.forename: Roy D
authors.initials: RD
authors.lastname: Magnuson
authors.forename: Daniel
authors.initials: D
authors.lastname: Charlier
authors.forename: Nico A J
authors.initials: NA
authors.lastname: van Nuland
authors.forename: Remy
authors.initials: R
authors.lastname: Loris
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D017101:Bacteriophage P1 / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D009875:Operator Regions, Genetic; D017434:Protein Structure, Tertiary; D053838:Scattering, Small Angle; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism*; D014961:X-Ray Diffraction
chemical_list: C083664:Doc protein, Enterobacteria phage P1; C083665:Phd protein, Enterobacteria phage P1; D014764:Viral Proteins; D004247:DNA