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Structural basis for distinct ligand-binding and targeting properties of the receptors DC-SIGN and DC-SIGNR

Abstract

Both the dendritic cell receptor DC-SIGN and the closely related endothelial cell receptor DC-SIGNR bind human immunodeficiency virus and enhance infection. However, biochemical and structural comparison of these receptors now reveals that they have very different physiological functions. By screening an extensive glycan array, we demonstrated that DC-SIGN and DC-SIGNR have distinct ligand-binding properties. Our structural and mutagenesis data explain how both receptors bind high-mannose oligosaccharides on enveloped viruses and why only DC-SIGN binds blood group antigens, including those present on microorganisms. DC-SIGN mediates endocytosis, trafficking as a recycling receptor and releasing ligand at endosomal pH, whereas DC-SIGNR does not release ligand at low pH or mediate endocytosis. Thus, whereas DC-SIGN has dual ligand-binding properties and functions both in adhesion and in endocytosis of pathogens, DC-SIGNR binds a restricted set of ligands and has only the properties of an adhesion receptor.

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Figure 1: Glycan array probed with fluorescein-labeled DC-SIGN and DC-SIGNR.
Figure 2: Oligosaccharides used in structural studies of DC-SIGN and DC-SIGNR.
Figure 3: DC-SIGN interactions with fucosylated and high-mannose oligosaccharides.
Figure 4: DC-SIGN and DC-SIGNR interactions with Lewisx and oligomannosides.
Figure 5: Binding of mutant DC-SIGN and DC-SIGNR to selected glycans.
Figure 6: pH-dependence of 125I-labeled Man30-BSA binding to immobilized DC-SIGN and DC-SIGNR.
Figure 7: Uptake and degradation of 125I-labeled Man30-BSA by cells expressing DC-SIGN and DC-SIGNR.

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Acknowledgements

We thank D. Torgersen for help with protein preparation and P. Lee for glycan array analysis. This work was supported by Wellcome Trust grant 041845 to K.D., a grant from the Mizutani Foundation for Glycoscience to W.I.W. and US National Institutes of Health grants GM50565 to W.I.W. and GM62116 to the Consortium for Functional Glycomics. Diffraction data were measured at the Advanced Light Source of the Lawrence Berkeley National Laboratory.

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Correspondence to Kurt Drickamer.

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Supplementary information

Supplementary Fig. 1

Polyacrylamide (PAA) derivatives in the glycan array probed with fluorescein-labeled DC-SIGN and DC-SIGNR. (PDF 139 kb)

Supplementary Fig. 2

Stereo views of bound carbohydrate in the final 2FoFc maps. (PDF 187 kb)

Supplementary Table 1

Identification of glycans on array. (PDF 19 kb)

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Guo, Y., Feinberg, H., Conroy, E. et al. Structural basis for distinct ligand-binding and targeting properties of the receptors DC-SIGN and DC-SIGNR. Nat Struct Mol Biol 11, 591–598 (2004). https://doi.org/10.1038/nsmb784

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