Structural analysis of carbohydrate binding by the macrophage mannose receptor CD206

Abstract

The human mannose receptor expressed on macrophages and hepatic endothelial cells scavenges released lysosomal enzymes, glycopeptide fragments of collagen, and pathogenic microorganisms and thus reduces damage following tissue injury. The receptor binds mannose, fucose, or N-acetylglucosamine (GlcNAc) residues on these targets. C-type carbohydrate-recognition domain 4 (CRD4) of the receptor contains the site for Ca 2+ -dependent interaction with sugars. To investigate the details of CRD4 binding, glycan array screening was used to identify oligosaccharide ligands. The strongest signals were for glycans that contain either Manα1-2Man constituents or fucose in various linkages. The mechanisms of binding to monosaccharides and oligosaccharide substructures present in many of these ligands were examined in multiple crystal structures of CRD4. Binding of mannose residues to CRD4 results primarily from interaction of the equatorial 3- and 4-OH groups with a conserved principal Ca 2+ common to almost all sugar-binding C-type CRDs. In the Manα1-2Man complex, supplementary interactions with the reducing mannose residue explain the enhanced affinity for this disaccharide. Bound GlcNAc also interacts with the principal Ca 2+ through equatorial 3- and 4-OH groups, whereas fucose residues can bind in several orientations, through either the 2- and 3-OH groups or the 3- and 4-OH groups. Secondary contacts with additional sugars in fucose-containing oligosaccharides, such as the Lewis-a trisaccharide, provide enhanced affinity for these glycans. These results explain many of the biologically important interactions of the mannose receptor with both mammalian glycoproteins and microbes such as yeast and suggest additional classes of ligands that have not been previously identified.

Macrophage targeted theranostic strategy for accurate detection and rapid stabilization of the inflamed high-risk plaque

“…As an MMR-targeted theranostic agent, the NIRF-emitting MMR carrier was prepared to specifically deliver lobeglitazone into plaque macrophages and scaled up for the translational application to the plaques in coronary-sized arteries. Previous studies have reported that D-mannose had higher binding affinity towards mannose receptors than other monosugars (i.e., N-acetylglucosamine, glucose, xylose, and galactose) 33 - 37 . In this study, we used mannosamine as a specific ligand to mannose receptors because it has the equatorial hydroxyl groups at both the C3 and C4 positions that are the principal determinants of recognition towards mannose receptors ( Figure S1 ).…”

A fresh trim provides a new look at the human mannose receptor

“…Glycan array screening revealed a fuller picture of the variety of glycans CRD4 is capable of binding. Nearly all the oligosaccharides giving a strong signal included a nonreducing D-mannose or L-fucose moiety (2). The identified D-mannose ligands are all substructures of a Man 9 high-mannose oligosaccharide, and the strongest D-mannose-related signals have terminal D-mannose-alpha-1,2-D-mannose motifs.…”

“…A solid-phase competition assay allowed the authors to delve more deeply into the glycan interactions. The data showed a Man 9 oligosaccharide binds with 40-fold higher affinity than a D-mannose monosaccharide (2). Testing of disaccharides and trisaccharides suggested that avidity could be responsible for the tighter binding of the branched ligands.…”

“…However, the molecular determinants driving carbohydrate recognition by the mannose receptor for its multitude of diverse carbohydrate ligands are not fully understood. New work by Feinberg et al (2) provides major advances on this front with high-resolution insight into the molecular determinants driving carbohydrate recognition across 15 crystal structures for one of the key carbohydratebinding domains from this receptor.…”

“…Figure1. CRD4 primary monosaccharide-binding site interactions demonstrating the promiscuous power of Ca 2+ coordination(2). Carbons of the interacting monosaccharide hydroxyl groups are labeled adjacently for all the complexes.…”