Structural basis for langerin recognition of diverse pathogen and mammalian glycans through a single binding site |
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Authors: | Feinberg Hadar Taylor Maureen E Razi Nahid McBride Ryan Knirel Yuriy A Graham Sarah A Drickamer Kurt Weis William I |
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Institution: | 1 Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA2 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA3 Division of Molecular Biosciences, Department of Life Sciences, Imperial College, London SW7 2AZ, UK4 Glycan Array Synthesis Core-D, Consortium for Functional Glycomics, Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA5 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia |
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Abstract: | Langerin mediates the carbohydrate-dependent uptake of pathogens by Langerhans cells in the first step of antigen presentation to the adaptive immune system. Langerin binds to an unusually diverse number of endogenous and pathogenic cell surface carbohydrates, including mannose-containing O-specific polysaccharides derived from bacterial lipopolysaccharides identified here by probing a microarray of bacterial polysaccharides. Crystal structures of the carbohydrate-recognition domain from human langerin bound to a series of oligomannose compounds, the blood group B antigen, and a fragment of β-glucan reveal binding to mannose, fucose, and glucose residues by Ca2+ coordination of vicinal hydroxyl groups with similar stereochemistry. Oligomannose compounds bind through a single mannose residue, with no other mannose residues contacting the protein directly. There is no evidence for a second Ca2+-independent binding site. Likewise, a β-glucan fragment, Glcβ1-3Glcβ1-3Glc, binds to langerin through the interaction of a single glucose residue with the Ca2+ site. The fucose moiety of the blood group B trisaccharide Galα1-3(Fucα1-2)Gal also binds to the Ca2+ site, and selective binding to this glycan compared to other fucose-containing oligosaccharides results from additional favorable interactions of the nonreducing terminal galactose, as well as of the fucose residue. Surprisingly, the equatorial 3-OH group and the axial 4-OH group of the galactose residue in 6SO4-Galβ1-4GlcNAc also coordinate Ca2+, a heretofore unobserved mode of galactose binding in a C-type carbohydrate-recognition domain bearing the Glu-Pro-Asn signature motif characteristic of mannose binding sites. Salt bridges between the sulfate group and two lysine residues appear to compensate for the nonoptimal binding of galactose at this site. |
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Keywords: | CRD carbohydrate-recognition domain Man4 Manα1-3(Manα1-6)Manα1-6Man Man5 Manα1-3(Manα1-6)Manα1-6(Manα1-3)Man PDB Protein Data Bank laminaritriose Glcβ1-3Glcβ1-3Glc PEG polyethylene glycol |
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