The structure of the iron import machinery from pathogenic Neisseria

Tuesday, October 25, 2011 — Poster Session II
Noon – 2:00 p.m.	Natcher Conference Center	NIDDK	STRUCTBIO-5

* FARE Award Winner

Authors

• N Noinaj
• N Easley
• N Mizuno
• J Gumbart
• E Boura
• S Buchanan

Abstract

Pathogenic Neisseria are responsible for causing gonorrhoea, meningococcal septicaemia, and bacterial meningitis. Neisseria must acquire iron for survival by hijacking iron from human sources. Two outer membrane proteins, TbpA (receptor and transporter) and TbpB (a lipoprotein co-receptor) work in concert to bind and extract iron specifically from human transferrin (hTF), making them primary targets for both drug and vaccine development. To aid these efforts, we determined the crystal structures of (1) TbpA in complex with hTF and (2) TbpB alone, identifying key residues and extracellular loops important for therapeutic development. We show that polyclonal antibodies against TbpA Loops 3, 7, and 11 and against a loop from the N-terminal plug domain were able to effectively block hTF binding by as much as 80% and polyclonal antibodies against full length TbpA could completely block hTF binding. An EM 3D reconstruction of the TbpA-TbpB-hTF complex, along with our crystal structures and SAXS analysis, allows us to provide the first glimpse of what the iron import machinery may look at the cell surface during infection. Together, our structural and biochemical studies allow us to propose a mechanism by which Neisseria are able to methodically hijack and import iron from hTF for its pathogenesis.

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