Cation-dependent Mannose-6-phosphate receptor
The cation-dependent mannose 6-phosphate receptor is one of two transmembrane receptors that bind mannose-6-phosphate on lysosomal proteins in the Golgi apparatus and direct their trafficking to the lysosome.. The other receptor is termed the cation-independent mannose-6-phosphate receptorand is also the receptor for Insulin-like growth factor II..
CFG Participating Investigators contributing to the understanding of this paradigm
- CFG Participating Investigators (PIs) with interest in mannose 6-phosphate receptors include: Ajit Varki
- Non-PIs using CFG resources to study mannose 6-phosphate receptors include: Nancy Dahms
Progress toward understanding this GBP paradigm
This section documents what is currently known about the cation-dependent mannose 6-phosphate receptor, its carbohydrate ligand(s), and how they interact to mediate cell communication.
The preferred ligands for the cation-dependent mannose 6-phosphate receptor are N-linked glycans that bear two terminal mannose 6-phosphate residues.
Cellular expression of GBP and ligands
The cation-dependent mannose 6-phosphate receptor is expressed in most cell types in mammals.
Biosynthesis of ligands
The signal for binding to the mannose 6-phosphate receptor is generated in several steps. GlcNAc phosphate is first added to the reducing end mannose in terminal Manα1-2Man disaccharides in N-linked glycans by N-acetylglucosaminephosphotransferase to generate phosphodiesters. Removal of the GlcNAc moieties by an N-acetylglucosaminidase, known as an uncapping enzymes, which generates phosphomonoesters, which are required for binding to the cation-dependent mannose 6-phosphate receptor. The mannose residues at the non-reducing termini can then be removed. There are typically two phosphomonoesters per N-linked glycan. 
The cation-dependent mannose 6-phosphate receptor has a luminal domain consisting of a single carbohydrate-recognition domain, and forms dimers in which these two domains typically interact with two mannose 6-phosphate residues on a single glycan. The crystal structure of the carbohydrate-recognition domain shows that the sugar moiety of mannose 6-phosphate makes hydrogen bonds to the hydroxyl groups at positions 2, 3 and 4, the orientations of which identify the sugar as mannose. The phosphate moiety makes hydrogen bonds with backbone atoms and interacts with a Mn2+ cation in the binding site.
Biological roles of GBP-ligand interaction
The CD-MPR is found in all eukaryotes and is known to play a highly conserved role in recognition and targeting of lysosomal enzymes. Both CD-MPRs and CI-MPRs are glycan-binding proteins that bind their M6P-tagged cargo in the lumen of the Golgi apparatus . Once bound to their cargo, the MPRs are recognized by the GGA family of clathrin adaptor proteins and accumulate in forming clathrin-coated vesicles. Upon arriving at the early endosome, the low pH environment of the endosome induces the MPRs release their cargo. The MPRs are recycled back to the Golgi, again by way of interaction with GGAs and vesicles. The cargo proteins are then trafficked to the lysosome via the late endosome in a process independent of the MPRs . Cargo molecules undergo extensive processing terminating in terminal mannose-6 phosphate on one or more arms of the oligosaccharide.
CFG resources used in investigations
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for Mannose-6-phosphate.
Probes for the cation-dependent mannose 6-phosphate receptor have been included on all versions of the glycogene micro-array.
Knockout mouse lines
The CFG did not generate mice deficient in the cation-dependent mannose-6-phosphate receptor gene, as these mice were created and published in 1993 . CD-M6PR-deficient mice are viable with no obvious developmental abnormalities. They exhibit high levels of phosphorylated lysosomal enzymes in serum and urine, indicating that these enzymes are being mis-sorted, a conclusion that was supported by studies in cultured cells from these mice.
In 2006, soluble forms of MPR were screened on the CFG glycan array (click here), but results were inconclusive.
The cation-dependent mannose 6-phosphate receptor has a single carbohydrate-recognition domain in the MRH family, while the cation-independent mannose 6-phosphate receptor has 15 such repeats, at least three of which bind mannose 6-phosphate.
- ↑ Sahagian, G. G. and Neufeld, E. F. Biosynthesis and turnover of the mannose 6-phosphate receptor in cultured Chinese hamster ovary cells. J Biol Chem 258, 7121-7128 (1983)
- ↑ Hoflack, B. and Kornfeld, S. Purification and characterization of a cation-dependent mannose 6-phosphate receptor from murine P388D1 macrophages and bovine liver. J Biol Chem 260, 12008-12014 (1985)
- ↑ Dahms, N. M. and Kornfeld, S. The cation-dependent mannose 6-phosphate receptor. Structural requirements for mannose 6-phosphate binding and oligomerization. J Biol Chem 264, 11458-11467 (1989)
- ↑ Nair, P., Schaub, B. E. and Rohrer, J. Characterization of the endosomal sorting signal of the cation-dependent mannose 6-phosphate receptor. J Biol Chem 278, 24753-24758 (2003)
- ↑ Sun, G., Zhao, H., Kalyanaraman, B. and Dahms, N. M. Identification of residues essential for carbohydrate recognition and cation dependence of the 46-kDa mannose 6-phosphate receptor. Glycobiology 15, 1136-1149 (2005)
- ↑ 6.0 6.1 6.2 Kim, J. J., Olson, L. J. and Dahms, N. M. Carbohydrate recognition by the mannose-6-phosphate receptors. Curr Opin Struct Biol 19, 534-542 (2009)
- ↑ Olson, L. J., Sun, G., Bohnsack, R. N., Peterson, F. C., Dahms, N. M. and Kim, J. J. Intermonomer interactions are essential for lysosomal enzyme binding by the cation-dependent mannose 6-phosphate receptor. Biochemistry 49, 236-246 (2010)
- ↑ Tong, P. Y., Tollefsen, S. E. and Kornfeld, S. The cation-independent mannose 6-phosphate receptor binds insulin-like growth factor II. J Biol Chem 263, 2585-2588 (1988)
- ↑ Lobel, P., Dahms, N. M. and Kornfeld, S. Cloning and sequence analysis of the cation-independent mannose 6-phosphate receptor. J Biol Chem 263, 2563-2570 (1988)
- ↑ Tong, P. Y. and Kornfeld, S. Ligand interactions of the cation-dependent mannose 6-phosphate receptor. Comparison with the cation-independent mannose 6-phosphate receptor. J Biol Chem 264, 7970-7975 (1989)
- ↑ Hancock, M. K., Yammani, R. D. and Dahms, N. M. Localization of the carbohydrate recognition sites of the insulin-like growth factor II/mannose 6-phosphate receptor to domains 3 and 9 of the extracytoplasmic region. J Biol Chem 277, 47205-47212 (2002)
- ↑ Bohnsack, R. N., Song, X., Olson, L. J., Kudo, M., Gotschall, R. R., Canfield, W. M., Cummings, R. D., Smith, D. F. and Dahms, N. M. Cation-independent mannose 6-phosphate receptor: a composite of distinct phosphomannosyl binding sites. J Biol Chem 284, 35215-35226 (2009)
- ↑ Brown, J., Jones, E. Y. and Forbes, B. E. Keeping IGF-II under control: lessons from the IGF-II-IGF2R crystal structure. Trends Biochem Sci 34, 612-619 (2009)
- ↑ Laube, F. Mannose-6-phosphate/insulin-like growth factor-II receptor in human melanoma cells: effect of ligands and antibodies on the receptor expression. Anticancer Res 29, 1383-1388 (2009)
- ↑ Song, X, Lasanajak, Y, Olson, LJ, Boonen, M, Dahms, NM, Kornfeld, S, Cummings, RD and Smith, DF (2009) Glycan microarray analysis of P-type lectins reveals distinct phospho-mannose glycan recognition J. Biol. Chem. 284, 35201-35214
- ↑ Dahms, NM, Olson, LJ and Kim, J-JP (2008) Strategies for carbohydrate recognition by the mannose 6-phosphate receptors. Glycobiology 18, 664–678
- ↑ Roberts, DL, Weix, DJ, Dahms, NM and Kim, J-JP (1998) Molecular Basis of Lysosomal Enzyme Recognition: Three-Dimensional Structure of the Cation-Dependent Mannose 6-Phosphate Receptor Cell 93, 639-648
- ↑ Ludwig T, Ovitt CE, Bauer U, Hollinshead M, Remmler J, Lobel P, Rüther U, Hoflack B. Targeted disruption of the mouse cation-dependent mannose 6-phosphate receptor results in partial missorting of multiple lysosomal enzymes. EMBO J. 1993 Dec 15;12(13):5225-35. PubMed PMID: 8262065; PubMed Central PMCID: PMC413788.
The CFG is grateful to the following PIs for their contributions to this wiki page: Kurt Drickamer, John Hanover