Structural basis for antibacterial peptide self‐immunity by the bacterial ABC transporter McjD

• Kiran Bountra ^[4] ; Gregor Hagelueken ^[1] ; Hassanul G Choudhury ^[4] ; Valentina Corradi ^[2] ; Kamel El Omari ^[3] ; Armin Wagner ^[3] ; Indran Mathavan ^[4] ; Séverine Zirah ^[5] ; Weixiao Yuan Wahlgren ^[6] ; D Peter Tieleman ^[2] ; Olav Schiemann ^[1] ; Sylvie Rebuffat ^[5] ; Konstantinos Beis ^[4]
  1. [1] University of Bonn

     University of Bonn

     Kreisfreie Stadt Bonn, Alemania

     
  2. [2] University of Calgary

     University of Calgary

     Canadá

     
  3. [3] Rutherford Appleton Laboratory

     Rutherford Appleton Laboratory

     South Oxfordshire District, Reino Unido

     
  4. [4] 1 Department of Life Sciences Imperial College London London UK; 2 Rutherford Appleton Laboratory Research Complex at Harwell Oxfordshire UK
  5. [5] 6 Communication Molecules and Adaptation of Microorganisms Laboratory (MCAM, UMR 7245 CNRS‐MNHN) Muséum National d'Histoire Naturelle Centre National de la Recherche Scientifique Sorbonne Universités Paris France
  6. [6] 1 Department of Life Sciences Imperial College London London UK; 2 Rutherford Appleton Laboratory Research Complex at Harwell Oxfordshire UK; 7 Chemistry & Molecular Biology University of Gothenburg Göteborg Sweden

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 36, Nº. 20, 2017, págs. 3062-3079
• Idioma: inglés
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  • Certain pathogenic bacteria produce and release toxic peptides to ensure either nutrient availability or evasion from the immune system. These peptides are also toxic to the producing bacteria that utilize dedicated ABC transporters to provide self‐immunity. The ABC transporter McjD exports the antibacterial peptide MccJ25 in Escherichia coli. Our previously determined McjD structure provided some mechanistic insights into antibacterial peptide efflux. In this study, we have determined its structure in a novel conformation, apo inward‐occluded and a new nucleotide‐bound state, high‐energy outward‐occluded intermediate state, with a defined ligand binding cavity. Predictive cysteine cross‐linking in E. coli membranes and PELDOR measurements along the transport cycle indicate that McjD does not undergo major conformational changes as previously proposed for multi‐drug ABC exporters. Combined with transport assays and molecular dynamics simulations, we propose a novel mechanism for toxic peptide ABC exporters that only requires the transient opening of the cavity for release of the peptide. We propose that shielding of the cavity ensures that the transporter is available to export the newly synthesized peptides, preventing toxic‐level build‐up.