Extensive DNA mimicry by the ArdA anti-restriction protein and its role in the spread of antibiotic resistance

• Published in: Nucleic acids research Vol. 37; no. 15; pp. 4887 - 4897
• Main Authors: McMahon, Stephen A, Roberts, Gareth A, Johnson, Kenneth A, Cooper, Laurie P, Liu, Huanting, White, John H, Carter, Lester G, Sanghvi, Bansi, Oke, Muse, Walkinshaw, Malcolm D, Blakely, Garry W, Naismith, James H, Dryden, David T.F
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.08.2009; Oxford Publishing Limited (England)
• Subjects: Amino Acid Sequence; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Crystallography, X-Ray; Deoxyribonucleases, Type I Site-Specific - antagonists & inhibitors; Dimerization; DNA - chemistry; DNA Restriction-Modification Enzymes - antagonists & inhibitors; Drug Resistance, Bacterial - genetics; Escherichia coli; Genome, Bacterial; Models, Molecular; Molecular Mimicry; Molecular Sequence Data; Protein Binding; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Site-Specific DNA-Methyltransferase (Adenine-Specific) - chemistry; Structural Biology
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkp478

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.