Structural basis for iron piracy by pathogenic Neisseria

Neisseria are obligate human pathogens causing bacterial meningitis, septicaemia and gonorrhoea. Neisseria require iron for survival and can extract it directly from human transferrin for transport across the outer membrane. The transport system consists of TbpA, an integral outer membrane protein, and TbpB, a co-receptor attached to the cell surface; both proteins are potentially important vaccine and therapeutic targets. Two key questions driving Neisseria research are how human transferrin is specifically targeted, and how the bacteria liberate iron from transferrin at neutral pH. To address these questions, we solved crystal structures of the TbpA–transferrin complex and of the corresponding co-receptor TbpB. We characterized the TbpB–transferrin complex by small-angle X-ray scattering and the TbpA–TbpB–transferrin complex by electron microscopy. Our studies provide a rational basis for the specificity of TbpA for human transferrin, show how TbpA promotes iron release from transferrin, and elucidate how TbpB facilitates this process. Structural analysis reveals the iron scavenging mechanism used by Neisseria species, involving TbpA and TbpB proteins, and sheds light on how human transferrin is specifically targeted. How Neisseria pathogens gather iron Pathogenic bacteria exploit a range of strategies to obtain iron from their host during infection. Neisseria species, including meningitis, septicaemia and gonorrhoea pathogens, express an outer membrane protein, TbpA, and a receptor protein, TbpB, that together can directly extract iron from human transferrin and facilitate iron uptake. The iron-scavenging mechanism is now revealed through structural analysis. The structures are relevant to drug and vaccine design.