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Bidirectional communication between nucleotide and substrate binding sites in a type IV multidrug ABC transporter
Victor Hugo Pérez Carrillo1, Margot Di Cesare2, Dania Rose-Sperling1
1Faculty of Chemistry and Earth Sciences, Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich Schiller University Jena, Humboldtstraße 10, 07743, Jena, Germany.
Nature Communications
|November 11, 2025
Summary
Researchers identified a key residue cluster in type IV ABC transporters that acts as a communication hinge. This hinge is crucial for coordinating ATP hydrolysis with substrate transport in multidrug resistance pumps.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- ATP-binding cassette (ABC) transporters utilize ATP for substrate transport across membranes.
- Type IV ABC transporters, including multidrug resistance (MDR) pumps, feature nucleotide-binding domains (NBDs) and transmembrane domains (TMDs) linked by intracellular domains with coupling helices.
- The precise mechanism coordinating ATP hydrolysis and substrate transport in these transporters remains largely unknown.
Purpose of the Study:
- To elucidate the functional coordination between ATP hydrolysis and substrate transport in type IV ABC transporters.
- To identify key molecular components involved in signal transduction between NBDs and TMDs.
Main Methods:
- Site-directed mutagenesis of the conserved residue cluster in the bacterial type IV MDR transporter BmrA.
- Functional assays to assess transport activity and ATP hydrolysis.
- Nuclear magnetic resonance (NMR) spectroscopy.
- Hydrogen-deuterium exchange mass spectrometry (HDX-MS).
- Photo-induced electron-transfer fluorescence correlation spectroscopy (PET-FCS).
Main Results:
- A conserved residue cluster at the NBD/TMD interface, centered on W413, was identified in BmrA.
- Mutation of W413 uncoupled ATP hydrolysis from transport activity, indicating its critical role.
- The identified cluster functions as a bidirectional communication hinge, relaying signals between NBDs and TMDs via coupling helix 2.
- Hinge mutations were shown to influence both local and global protein dynamics, thereby affecting transporter activity.
Conclusions:
- The study uncovers a novel allosteric pathway critical for functional coupling in multidomain ABC transporters.
- The identified communication hinge is essential for coordinating ATP hydrolysis with substrate translocation.
- These findings provide fundamental insights into the mechanism of action for a broad class of essential membrane transporters.
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