The mycobacterial ABC transporter IrtAB employs a membrane-facing crevice for siderophore-mediated iron uptake

Imre Gonda, Simona Sorrentino, Laura Galazzo, Nicolas P. Lichti, Fabian M. Arnold, Ahmad R. Mehdipour, Enrica Bordignon () and Markus A. Seeger ()
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Imre Gonda: University of Zurich
Simona Sorrentino: University of Zurich
Laura Galazzo: University of Geneva
Nicolas P. Lichti: University of Zurich
Fabian M. Arnold: University of Zurich
Ahmad R. Mehdipour: Ghent University
Enrica Bordignon: University of Geneva
Markus A. Seeger: University of Zurich

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract The mycobacterial ABC transporter IrtAB features an ABC exporter fold, yet it imports iron-charged siderophores called mycobactins. Here, we present extensive cryo-EM analyses and DEER measurements, revealing that IrtAB alternates between an inward-facing and an outward-occluded conformation, but does not sample an outward-facing conformation. When IrtAB is locked in its outward-occluded conformation in nanodiscs, mycobactin is bound in the middle of the lipid bilayer at a membrane-facing crevice opening at the heterodimeric interface. Mutations introduced at the crevice abrogate mycobactin import and in corresponding structures, the crevice is collapsed. A conserved triple histidine motif coordinating a zinc ion is present below the mycobactin binding site. Substitution of these histidine residues with alanine results in a decoupled transporter, which hydrolyzes ATP, but lost its capacity to import mycobactins. Our data suggest that IrtAB imports mycobactin via a credit-card mechanism in a transport cycle that is coupled to the presence of zinc.

Date: 2025
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DOI: 10.1038/s41467-024-55136-7

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