Structural insights into the mechanism underpinning iron piracy in pathogenic <i>Neisseria</i>.

Abstract

The pathogenesis of <i>Neisseria</i> hinges on the surface proteins TbpA and TbpB, which orchestrate the acquisition of iron from transferrin. TbpB selectively captures iron-loaded transferrin and delivers it to TbpA for iron import. We report a series of cryo-electron microscopy structures of trapped intermediates along the iron acquisition pathway. These structural studies are supported by pulldowns, electron paramagnetic resonance studies, molecular dynamics simulations, and studies in <i>Neisseria gonorrhoeae</i>, which show that TbpA mechanically opens the C-lobe of transferrin, triggering iron release. Once iron is removed, TbpB dissociates and undergoes large subunit rearrangements with its C-lobe rebinding at a different interface on transferrin. TonB binding expands the barrel of TbpA, helping displace the plug to open a path for iron import. This also disrupts the interaction of the plug loop with the C1 domain of transferrin, leading to the dissociation of the spent transferrin. Together, our study provides a more complete understanding of metal acquisition systems in <i>Neisseria</i> and other Gram-negative bacteria.