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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 UPARAP, M-type PLA2R, and DEC-205 (CD205).
The receptor recognises terminal mannose, N-acetylglucosamine and fucose residues on attached to proteins found on the surface of some , playing a role in both the innate and adaptive immune systems. Additional functions include clearance of glycoproteins from circulation, including sulphated glycoprotein and glycoproteins released in response to pathology 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 proteolysis to its active form in the Golgi apparatus. In general, 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.
Other ligands include chondroitin sulfates A and B, as well as sulphated sialyl-LewisX and sialyl-Lewis A structures. The mannose receptor is the only member of the family in which this domain is functional.
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 evolution 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 .
Alternatively, interactions between neighbouring CRDs may hold them in close proximity to one another and cause the extracellular region of the receptor to bend, bringing the N-terminal cysteine-rich domain into close contact with the CRDs. This would position CRDs 4 and 5 furthest from the membrane to maximise their interaction with potential ligands. The resistance to proteolysis shown by CRDs 4 and 5 suggests physical interactions between the two domains does occur, thereby supporting the existence of this U-shaped conformation.
It is thought that transitions between these two conformations occur in a pH-dependent manner, regulating ligand selectivity and release during endocytosis. The lower, more acidic pH of early endosomes is thought to be responsible for ligand release.
The soluble protein consists of the entire extracellular region of the receptor and it may be involved in transport of mannosylated proteins away from sites of inflammation. Shedding of the mannose receptor from macrophages has been shown to be enhanced upon recognition of fungal pathogens such as Candida albicans and Aspergillus fumigatus, which suggests the soluble form may play a role in fungal pathogen recognition. In this way, the balance between membrane-bound and soluble mannose receptor could affect targeting of fungal pathogens during the course of infection.
Surprisingly, mannose receptor knockout mouse do not show increased susceptibility to infection, which suggests that the receptor is not essential for phagocytosis. However, its involvement cannot be rejected since other mechanisms may compensate. For example, infection of knockout mice with P. carinii resulted in increased recruitment of macrophages to the site of infection. Furthermore, other receptors present on the surface of phagocytic cells, such as DC-SIGN, SIGNR1 and Endo180, exhibit similar ligand binding ability to the mannose receptor and so it is likely that in its absence, these proteins are able to compensate and induce phagocytosis.
The ability of the mannose receptor to aid in pathogen internalisation is also thought to facilitate infection by Mycobacterium tuberculosis and Mycobacterium leprae. These bacteria reside and multiply in macrophages, preventing formation of the phagolysosome to avoid degradation. Hence, by mediating their entrance into the macrophage, blocking the mannose receptor helps these pathogens to infect and grow in their target cell.
As opposed to macrophages that use the mannose receptors for phagocytosis of particulate matter >200 nm, the mannose receptor on liver sinusoidal endothelial cells mediates clathrin-mediated endocytosis of macromolecules and nanoparticles <200 nm.
Mature dendritic cells and macrophages use the mannose receptor for antigen presentation in a different way. The cleaved, soluble receptor binds to circulating antigens and directs them to effector cells in lymphatic system via its cysteine-rich domain, thus activating the adaptive immune system.
High-mannose oligosaccharides present on the surface of these glycoproteins act to mark their transient nature, since they are eventually recognised by the mannose receptor and removed from the circulation. Mannose receptor knockout mice are less able to clear these proteins, and show increased concentrations of a number of lysosomal hydrolases in the blood.
Consistent with this function, the mannose receptor is expressed at low levels during inflammation and at high levels during the resolution of inflammation, to ensure inflammatory agents are removed from the circulation only at the appropriate time.
Glycoprotein hormones such as lutropin, which triggers release of the egg during ovulation, must stimulate their receptors in pulses to avoid receptor desensitisation. Glycans on their surface are capped with sulphated N-Acetylgalactosamine (GalNAc), making them ligands for the cysteine-rich ricin homology domain of the mannose receptor. This tag ensures a cycle of release, stimulation, and removal from the circulation.
Knockout mice lacking the enzyme required to add the sulphated GalNAc capping structure show longer half-lives for lutropin, which results in increased receptor activation and oestrogen production. Female knockout mice reach sexual maturity faster than their wild-type counterparts, have a longer oestrus cycle and produce more litters. Thus, the sulphated GalNAc tag is very important in regulating serum concentrations of certain glycoprotein hormones.
| C-type mannose receptor 1, C-type lectin domain family 13 member D (CLEC13D), CD206, MMR |
| C-type mannose receptor 2, Urokinase-type plasminogen activator receptor-associated protein, CD280 |
MRC2/Endo180 interacts with Basigin/CD147 via its fourth C-type lectin domain to form a molecular epithelial-mesenchymal transition suppressor complex that if disrupted results in the induction of invasive prostate epithelial cell behavior associated with poor prostate cancer survival. Increased basement membrane stiffness due to its glycation can also trigger Endo180-dependent invasion of prostate epithelial cells and this bio-mechanical mechanism is associated with poor prostate cancer survival. It has been suggested that stabilization of the Endo180-CD147 epithelial-mesenchymal transition suppressor complex and targeting of the non-complexed form of Endo180 in invasive cells could have therapeutic benefit in the prevention of cancer progression and metastasis.
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