Mannose receptor

The mannose receptor (Cluster of Differentiation 206, CD206) is a C-type lectin primarily present on the surface of macrophages, immature dendritic cells and liver sinusoidal endothelial cells, but is also expressed on the surface of skin cells such as human dermal fibroblasts and keratinocytes. It is the first member of a family of endocytic receptors that includes Endo180 (CD280), M-type PLA2R, and DEC-205 (CD205). The mannose receptor (Cluster of Differentiation 206, CD206) is a C-type lectin primarily present on the surface of macrophages, immature dendritic cells and liver sinusoidal endothelial cells, but is also expressed on the surface of skin cells such as human dermal fibroblasts and keratinocytes. It is the first member of a family of endocytic receptors that includes Endo180 (CD280), M-type PLA2R, and DEC-205 (CD205). The receptor recognises terminal mannose, N-acetylglucosamine and fucose residues on glycans attached to proteins found on the surface of some microorganisms, playing a role in both the innate and adaptive immune systems. Additional functions include clearance of glycoproteins from the circulation, including sulphated glycoprotein hormones and glycoproteins released in response to pathological events. The mannose receptor recycles continuously between the plasma membrane and endosomal compartments in a clathrin-dependent manner. The mannose receptor is a type I transmembrane protein, with an extracellular N-terminus and an intracellular C-terminus. It is first synthesised as an inactive precursor, but is proteolytically cleaved to its active form in the Golgi apparatus. The extracellular portion of the receptor is composed of 8 consecutive C-type carbohydrate recognition domains (CRDs) closest to the plasma membrane, followed by a single fibronectin type II repeat domain and an N-terminal cysteine-rich domain. The cytoplasmic tail is not capable of signal transduction in isolation, since it lacks the appropriate signaling motifs. The N-terminal cysteine-rich domain is homologous to the ricin B chain and binds to sulphated sugar moieties, with particularly high affinity for N-Acetylgalactosamine and galactose residues sulphated at positions 3 and 4 of their pyranose rings. Other ligands include chondroitin sulfates A and B, as well as sulphated Lewisx and Lewisa structures. The mannose receptor is the only member of the family in which this domain is functional. The fibronectin type II repeat domain is conserved amongst all members of the mannose receptor family. Collagens I-IV bind this region with high affinity, while collagen V binds only weakly. Through this domain, the mannose receptor internalises collagen in macrophages and liver sinusoidal cells, independent of the lectin activity of the receptor. Along with the N-terminal cysteine-rich domain, this domain is the most highly conserved between mice and humans (92%). The 8 tandem CRDs in the extracellular region of the mannose receptor share only 30% homology with each other. They each contain at least some of the amino acid residues necessary for Ca2+ and ligand binding, common to functional C-type CRDs. Only CRDs 4 and 5 contain all of the residues required for sugar binding, forming a protease-resistant ligand-binding core. The most common ligand is terminal mannose residues, but N-acetylglucosamine and fucose also bind. The main interaction between CRD-4 and its sugar ligand is through direct ligation to the conserved Ca2+ in the sugar-binding site, in a similar way to the binding mechanism of mannan-binding lectin (MBL). However, a quarter of the free energy of sugar-binding is associated with the hydrophobic stacking interactions formed between one face of the sugar ring and the side chain of a conserved tyrosine residue in the binding site, which is not seen in MBL. Despite the similarities in mannose-binding between the mannose receptor and MBL, these differences suggest that mannose-binding by the mannose receptor evolved separately to that of other C-type lectins. Individually, the CRDs bind mannose with only weak affinity. High affinity binding is thought to result from the clustering of multiple CRDs. This clustering allows for binding of multivalent, branched ligands such as high-mannose N-linked oligosaccharides.