Journal
SCIENTIFIC REPORTS
Volume 9, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41598-019-48579-2
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Funding
- University of Oslo
- Norwegian Research Council [247730]
- iNEXT
- Norwegian Graduate School in Biocatalysis (BioCat)
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Cholera is a life-threatening diarrhoeal disease caused by the human pathogen Vibrio cholerae. Infection occurs after ingestion of the bacteria, which colonize the human small intestine and secrete their major virulence factor - the cholera toxin (CT). The GM1 ganglioside is considered the primary receptor of the CT, but recent studies suggest that also fucosylated receptors such as histo-blood group antigens are important for cellular uptake and toxicity. Recently, a special focus has been on the histo-blood group antigen Lewis(x) (Le(x)), however, where and how the CT binds to Le(x) remains unclear. Here we report the high-resolution crystal structure (1.5 angstrom) of the receptor-binding B-subunits of the CT bound to the Le(x) trisaccharide, and complementary quantitative binding data for CT holotoxins. Le(x), and also l-fucose alone, bind to the secondary binding site of the toxin, distinct from the GM1 binding site. In contrast, fucosyl-GM1 mainly binds to the primary binding site due to high-affinity interactions of its GM1 core. Le(x) is the first histo-blood group antigen of non-secretor phenotype structurally investigated in complex with CT. Together with the quantitative binding data, this allows unique insight into why individuals with non-secretor phenotype are more prone to severe cholera than so-called 'secretors'.
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