The properties of the human macrophage
galactose receptor have been investigated. Specificity for N-
acetylgalactosamine (GalNAc) residues with exposed 3- and 4-hydroxyl groups explains virtually all of the results obtained from a recently expanded array of synthetic
glycans and is consistent with a model for the structure of the binding site. This simple interaction is sufficient to explain the ability of the receptor to bind to
tumor-cell
glycans bearing Tn and sialyl-Tn
antigens, but not to more elaborate O-linked
glycans that predominate on normal cells. This specificity also allows for binding of parasite
glycans and screening of an array of bacterial outer membrane
oligosaccharides confirms that the receptor binds to a subset of these structures with appropriately exposed GalNAc residues. A key feature of the receptor is the clustering of binding sites in the extracellular portion of the
protein, which retains the trimeric structure observed in the cell membrane. Chemical crosslinking, gel filtration, circular dichroism analysis and differential scanning calorimetry demonstrate that this trimeric structure of the receptor is stabilized by an α-helical coiled coil that extends from the surface of the membrane to the globular
carbohydrate-recognition domains. The helical neck domains form independent trimerization domains. Taken together, these results indicate that the macrophage
galactose receptor shares many of the features of serum
mannose-binding protein, in which clusters of
monosaccharide-binding sites serve as detectors for a simple
epitope that is not common on endogenous cell surface
glycans but that is abundant on the surfaces of
tumor cells and certain pathogens.