Skip to: main navigation | content

SLAC National Accelerator Laboratory

Structural Basis for Iron Piracy by Pathogenic Neisseria
January 2013 SSRL Science Summary by Lori Ann White, SLAC Office of Communications

(Courtesy of the Buchanan Lab NIDDK, NIH)
Of the 11 species of Neisseria bacteria that colonize humans, 9 of them coexist peacefully with us. However, two can cause serious diseases N. gonorrhoeae, responsible for the sexually transmitted disease gonorrhea, and N. meningitidis, which causes septicemia and meningitis. Commercially available vaccines exist for four of the five known disease-causing serogroups of N. meningitidis (A, B, C, Y, W135) but no vaccine exists to combat serogroup B (menB); nor is there a vaccine available against N. gonorrhoeae. One target for vaccine development against menB and N. gonorrhoeae is the iron transporters found on the pathogens' surfaces. Cut off their access to iron and these pathogens cannot survive.

This study documents the crystal structures of two of the surface receptors of menB, TbpA and TbpB, which are used specifically by Neisseria to pirate iron from the abundant human iron binding protein, transferrin, during pathogenesis. Remarkably, TbpA was crystallized in complex with human transferrin, which allowed a precise description of the interactions between the Neisserial TbpA and the human transferrin protein, and enabled the identification of a helix finger and plug loop that are crucial for function. Attempts to crystallize the TbpB-transferrin complex were unsuccessful, but SAXS analysis based on data collected at SSRL's Beam Line 4-2 proved instrumental in constructing a model for how the Neisserial co-receptor was able to interact with human transferrin at the cell surface, revealing that TbpA and TbpB could simultaneously bind transferrin at distinct sites.

Based on the X-ray crystallography and SAXS results, the fully assembled Neisserial transferrin-iron import complex (TbpA-TbpB-transferrin) was modeled and EM studies performed to look at it experimentally. Here, purified complex was used for negative-stain EM analysis to produce class averages of the complex. These class averages were found to be consistent with the model for the fully assembled Neisserial transferrin-iron import complex, allowing a first glimpse at what the transferrin-iron import complex looks like at the Neisserial surface during its pathogenesis. As the iron transporters are usually well-conserved across Neisserial strains and generally do not undergo significant genetic variation, this picture could very likely hold for N. gonorrhoeae, the other pathogenic Neisserial strain, as well.


Primary Citation

N. Noinaj, N. C. Easley, M. Oke, N. Mizuno, J. Gumbart, E. Boura, A. N. Steere, O. Zak, P. Aisen, E. Tajkhorshid, R. W. Evans, A. R. Gorringe, A. B. Mason, A. C. Steven, S. K. Buchanan, "Structural Basis for Iron Piracy by Pathogenic Neisseria". Nature 483, 53 (2012). [DOI:10.1038/nature10823]

Related Links


Susan Buchanan, Laboratory of Molecular Biology NIDDK, NIH

2575 Sand Hill Road, MS: 99, Menlo Park, California, 94025, USA Tel: 650-926-4000 | Fax: 650-926-4100