Burkholderia cenocepacia epigenetic regulator M.BceJIV simultaneously engages two DNA recognition sequences for methylation

Richard Quintana-Feliciano, Jithesh Kottur (), Mi Ni, Rikhia Ghosh, Leslie Salas-Estrada, Goran Ahlsen, Olga Rechkoblit, Lawrence Shapiro, Marta Filizola, Gang Fang and Aneel K. Aggarwal ()
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Richard Quintana-Feliciano: Icahn School of Medicine at Mount Sinai
Jithesh Kottur: Icahn School of Medicine at Mount Sinai
Mi Ni: Icahn School of Medicine at Mount Sinai
Rikhia Ghosh: Icahn School of Medicine at Mount Sinai
Leslie Salas-Estrada: Icahn School of Medicine at Mount Sinai
Goran Ahlsen: Department of Biochemistry and Molecular Biophysics Columbia University Vagelos College of Physicians and Surgeons
Olga Rechkoblit: Icahn School of Medicine at Mount Sinai
Lawrence Shapiro: Department of Biochemistry and Molecular Biophysics Columbia University Vagelos College of Physicians and Surgeons
Marta Filizola: Icahn School of Medicine at Mount Sinai
Gang Fang: Icahn School of Medicine at Mount Sinai
Aneel K. Aggarwal: Icahn School of Medicine at Mount Sinai

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Burkholderia cenocepacia is an opportunistic and infective bacterium containing an orphan DNA methyltransferase called M.BceJIV with roles in regulating gene expression and motility of the bacterium. M.BceJIV recognizes a GTWWAC motif (where W can be an adenine or a thymine) and methylates N6 of the adenine at the fifth base position. Here, we present crystal structures of M.BceJIV/DNA/sinefungin ternary complex and allied biochemical, computational, and thermodynamic analyses. Remarkably, the structures show not one, but two DNA substrates bound to the M.BceJIV dimer, with each monomer contributing to the recognition of two recognition sequences. We also show that methylation at the two recognition sequences occurs independently, and that the GTWWAC motifs are enriched in intergenic regions in the genomes of B. cenocepacia strains. We further computationally assess the interactions underlying the affinities of different ligands (SAM, SAH, and sinefungin) for M.BceJIV, as a step towards developing selective inhibitors for limiting B. cenocepacia infection.

Date: 2024
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DOI: 10.1038/s41467-024-52130-x

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