Molecular Basis of the Differences in Binding Properties of the Highly Related C-type Lectins DC-SIGN and L-SIGN to Lewis X Trisaccharide and Schistosoma mansoni Egg Antigens

Abstract

The dendritic cell-specific C-type lectin DC-SIGN functions as a pathogen receptor that recognizes Schistosoma mansoni egg antigens through its major glycan epitope Gal␤1,4(Fuc␣1,3)GlcNAc (Le x ). Here we report that L-SIGN, a highly related homologue of DC-SIGN found on liver sinusoidal endothelial cells, binds to S. antigens. These data demonstrate for the first time that DC-SIGN and L-SIGN differ in their carbohydrate binding profiles and will contribute to our understanding of the functional roles of these C-type lectin receptors, both in recognition of pathogen and self-glycan antigens.

DC-SIGN Mediates Binding of Dendritic Cells to Authentic Pseudo-LewisY Glycolipids of Schistosoma mansoni Cercariae, the First Parasite-specific Ligand of DC-SIGN

“…From the proposed models it appears that Val 351 in DC-SIGN is close to the fucose binding site and makes a strong hydrophobic contact with CH at position 1 and 2 of fucose (38). By molecular modeling, in combination with binding studies of cell-surface expressed recombinant wild-type and mutant forms of DC-SIGN and its homologue L-SIGN (liver/lymph node-specific ICAM-3 grabbing nonintegrin), we found very similar results for the binding mode of Le X in DC-SIGN (31). Both models predict that a substituent on the 3-OH group of galactose would give a steric conflict with the side chain of Phe 313 , which is line with the results of binding studies that showed that 3Ј-sialylation or sulfation of Le X abrogates binding (43).…”

“…Recently more insight was obtained into the ability of DC-SIGN to bind fucosylated ligands (31,38). Analysis of crystals of the CRD of DC-SIGN bound to lacto-N-fucopentaose III (that comprises the Le X trisaccharide) showed that the 3-and 4-OH groups of the ␣1-3-linked fucose form coordination bonds with Ca 2ϩ in the primary binding site.…”

Internalizing Antibodies to the C-Type Lectins, L-SIGN and DC-SIGN, Inhibit Viral Glycoprotein Binding and Deliver Antigen to Human Dendritic Cells for the Induction of T Cell Responses

“…Current data support the idea that the interaction allows HIV and HCV to be transmitted in trans to other cells, e.g., T cells and hepatocytes (4,5,15), whereas it is thought to result in direct infection by other viruses, e.g., Ebola and SARS (12,16). Recently, L-SIGN has also been shown to serve as a receptor for bacterial pathogens, e.g., Mycobacterium tuberculosis (17) and parasites such as Schistosoma mansoni (18). Because liver sinusoidal endothelial cells (LSECs) are involved in tolerance induction, the use of L-SIGN receptor as a point of entry may explain the difficulty that the immune system has in eradicating these pathogens.…”

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

“…In this study, we highlighted the importance of CLR and TLR in the T-cell response we observed to SEA. Schistosome-derived products have been shown to bind both CLR and TLR on APC with roles identified for both TLR2 and DC-SIGN in the human and TLR2 in mice [14][15][16][17]26]. In this study, we provided evidence that in addition to its effects on DC, SEA also mediated effects directly on CD4 1 T cells, inducing surface-bound LAP and expression of the CLR DEC-205 and galectin-3 on T cells from NOD but not C57BL/6 mice ( Fig.…”