Bidirectional communication between nucleotide and substrate binding sites in a type IV multidrug ABC transporter

Victor Hugo Pérez Carrillo, Margot Di Cesare, Dania Rose-Sperling, Waqas Javed, Hannes Neuweiler, Julien Marcoux, Cédric Orelle (), Jean-Michel Jault () and Ute A. Hellmich ()
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Victor Hugo Pérez Carrillo: Friedrich Schiller University Jena
Margot Di Cesare: UMR 5086 CNRS/University of Lyon
Dania Rose-Sperling: Friedrich Schiller University Jena
Waqas Javed: UMR 5086 CNRS/University of Lyon
Hannes Neuweiler: Am Hubland
Julien Marcoux: Université de Toulouse
Cédric Orelle: UMR 5086 CNRS/University of Lyon
Jean-Michel Jault: UMR 5086 CNRS/University of Lyon
Ute A. Hellmich: Friedrich Schiller University Jena

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract ATP-binding cassette (ABC) transporters use ATP to transport substrates across membranes. In type IV ABC transporters, which include many multidrug resistance (MDR) pumps, communication between nucleotide-binding domains (NBDs) and transmembrane domains (TMDs) is mediated via large intracellular domains containing ‘coupling helices’. However, how ATP hydrolysis and substrate transport are functionally coordinated remains unclear. In the bacterial type IV MDR transporter BmrA, we identify a conserved residue cluster at the NBD/TMD interface centered on W413. Mutation of this tryptophan uncouples ATP hydrolysis from transport activity. Mutagenesis, functional assays, nuclear magnetic resonance spectroscopy, hydrogen-deuterium exchange mass spectrometry, and photo-induced electron-transfer fluorescence correlation spectroscopy show that the cluster forms a bidirectional communication hinge that relays signals between the NBD and TMD via coupling helix 2. Hinge mutations affect both local and global dynamics thereby influencing transporter activity. These findings uncover an allosteric pathway critical for functional coupling in multidomain ABC transporters.

Date: 2025
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DOI: 10.1038/s41467-025-65037-y

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