Molecular Insights into DC-SIGN Binding to Self-Antigens: The Interaction with the Blood Group A/B Antigens

TLDR

DC‑SIGN is a key dendritic‑cell receptor that, beyond pathogen recognition, binds endogenous glycans such as LeX and histo‑blood group antigens with α1‑2‑linked fucose, illustrating its glycan‑binding promiscuity. The study aimed to elucidate the atomic details of DC‑SIGN interaction with blood group A and B antigens in solution. NMR spectroscopy revealed that fucose coordinates the primary Ca²⁺ ion via its 3‑OH and 4‑OH groups, defining a single binding mode. The terminal αGal/αGalNAc contributes only marginal polar contacts but provides a hydrophobic pocket for V351, while αGal alone binds weakly, suggesting an additional binding mode for blood group B but not A.

Abstract

The dendritic cell-specific intracellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) is an important receptor of the immune system. Besides its role as pathogen recognition receptor (PRR), it also interacts with endogenous glycoproteins through the specific recognition of self-glycan epitopes, like LeX. However, this lectin represents a paradigmatic case of glycan binding promiscuity, and it also has been shown to recognize antigens with α1−α2 linked fucose, such as the histo blood group antigens, with similar affinities to LeX. Herein, we have studied the interaction in solution between DC-SIGN and the blood group A and B antigens, to get insights into the atomic details of such interaction. With a combination of different NMR experiments, we demonstrate that the Fuc coordinates the primary Ca2+ ion with a single binding mode through 3-OH and 4-OH. The terminal αGal/αGalNAc affords marginal direct polar contacts with the protein, but provides a hydrophobic hook in which V351 of the lectin perfectly fits. Moreover, we have found that αGal, but not αGalNAc, is a weak binder itself for DC-SIGN, which could endow an additional binding mode for the blood group B antigen, but not for blood group A.