title: Extensive DNA mimicry by the ArdA anti-restriction protein and its role in the spread of antibiotic resistance.
abstract: The ardA gene, found in many prokaryotes including important pathogenic species, allows associated mobile genetic elements to evade the ubiquitous Type I DNA restriction systems and thereby assist the spread of resistance genes in bacterial populations. As such, ardA contributes to a major healthcare problem. We have solved the structure of the ArdA protein from the conjugative transposon Tn916 and find that it has a novel extremely elongated curved cylindrical structure with defined helical grooves. The high density of aspartate and glutamate residues on the surface follow a helical pattern and the whole protein mimics a 42-base pair stretch of B-form DNA making ArdA by far the largest DNA mimic known. Each monomer of this dimeric structure comprises three alpha-beta domains, each with a different fold. These domains have the same fold as previously determined proteins possessing entirely different functions. This DNA mimicry explains how ArdA can bind and inhibit the Type I restriction enzymes and we demonstrate that 6 different ardA from pathogenic bacteria can function in Escherichia coli hosting a range of different Type I restriction systems.
authors.affiliation: Centre for Biomolecular Science, The University, St Andrews KY16 9ST, UK.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: McMahon
authors.forename: Gareth A
authors.initials: GA
authors.lastname: Roberts
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Johnson
authors.forename: Laurie P
authors.initials: LP
authors.lastname: Cooper
authors.forename: Huanting
authors.initials: H
authors.lastname: Liu
authors.forename: John H
authors.initials: JH
authors.lastname: White
authors.forename: Lester G
authors.initials: LG
authors.lastname: Carter
authors.forename: Bansi
authors.initials: B
authors.lastname: Sanghvi
authors.forename: Muse
authors.initials: M
authors.lastname: Oke
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Walkinshaw
authors.forename: Garry W
authors.initials: GW
authors.lastname: Blakely
authors.forename: James H
authors.initials: JH
authors.lastname: Naismith
authors.forename: David T F
authors.initials: DT
authors.lastname: Dryden
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry; D015280:DNA Restriction-Modification Enzymes / Q000037:antagonists & inhibitors*; D015253:Deoxyribonucleases, Type I Site-Specific / Q000037:antagonists & inhibitors; D019281:Dimerization; D024881:Drug Resistance, Bacterial / Q000235:genetics; D016680:Genome, Bacterial; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific) / Q000737:chemistry
chemical_list: D001426:Bacterial Proteins; D015280:DNA Restriction-Modification Enzymes; D004247:DNA; C093244:DNA modification methylase EcoKI; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific); D015253:Deoxyribonucleases, Type I Site-Specific