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A non-human glycan mediates human susceptibility to a bacterial toxin

Jamie Rossjohn group (Monash University) and collaborators


The groups of Jamie Rossjohn and Travis Beddoe at Monash University, and collaborators, investigated the structure of subtilase cytotoxin (SubAB), which is secreted by Shiga toxigenic Escherichia coli (STEC) and causes serious gastrointestinal disease in humans. SubAB is an AB5 toxin in which the pentameric B subunits direct target-cell uptake by binding cell surface glycans, and the A subunit is transported into the cell where it disrupts specific eukaryotic cell functions. The SubAB A subunit cleaves an essential ER chaperone, leading to toxicity. Surprisingly the pentameric B subunits of SubAB have a strong preference to bind glycans terminating in sialic acid N-glycolylneuraminic acid (Neu5Gc), which is not synthesized in humans. The structure of SubAB with bound Neu5Gc explains this specificity. Although not synthesized in humans, Neu5Gc is found in red meats and dairy products, which have been associated with SubAB-producing STEC contamination.

Figure: (A) Pentameric SubB-Neu5Gc structure with protomers color-coded (sugars in cyan). (B) Side view of SubB:Neu5Gcα2-3Galβ1GlcNAcβProN3 (cyan sugars). (C) Side view of the related cholera toxin subunit B:GM1 (cyan ligands).


Byres, E, Paton, AW, Paton, JC, Löfling, JC, Smith, DF, Wilce, MCJ, Talbot, UM, Chong, DC, Yu, H, Huang, S, Chen, X, Varki, NM, Varki, A, Rossjohn, J, Beddoe, T. Incorporation of a non-human glycan mediates human susceptibility to a bacterial toxin, Nature 456, 648-652 (2008). DOI: 10.1038/nature07428

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