Cation-dependent Mannose-6-phosphate receptor

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The mannose 6-phosphate receptor, also referred to as the cation-dependent mannose 6-phosphate receptor or CD-MPR, is one of two transmembrane proteins that bind mannose-6-phosphate (M6P) on lysosomal proteins in the Golgi apparatus that are destined for transport to the lysosome[1][2][3][4][5][6][7]. The other protein is termed the cation-independent mannose-6-phosphate receptor or (CI-MPR) and is also the receptor for Insulin-like growth factor II[8][9][10][11][12][13][14].

Contents

CFG Participating Investigators contributing to the understanding of this paradigm

  • CFG Participating Investigators (PIs) with interest in CD-MPR include: Ajit Varki
  • Non-PIs using CFG resources to study the CD-MPR 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.

Carbohydrate ligands

The cation-dependent mannose-6-phosphate receptor binds mannose-6-phosphate (M6P). The CD-MPR shows enhanced binding to M6P in the presence of divalent cations, such as manganese[7][15]. The CD-MPR binds M6P on lysosomal proteins in the Golgi apparatus that are destined for transport to the lysosome (see above).

Cellular expression of GBP and ligands


Biosynthesis of ligands


Structure


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 [6]. 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 [6]. 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.

Glycan profiling


Glycogene microarray


Knockout mouse lines


Glycan array

In 2006, soluble forms of MPR were screened on the CFG glycan array (click here), but results were inconclusive.

Related GBPs

The cation-independent Mannose-6-phosphate (CI-M-6-P) receptor has a shared motif with the CD-MPR.

References

  1. ↑ 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)
  2. ↑ 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)
  3. ↑ 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)
  4. ↑ 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)
  5. ↑ 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. ↑ 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)
  7. ↑ 7.0 7.1 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)
  8. ↑ 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)
  9. ↑ 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)
  10. ↑ 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)
  11. ↑ 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)
  12. ↑ 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)
  13. ↑ 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)
  14. ↑ 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)
  15. ↑ Faro, J., Chen, Y., Jhaveri, P., Oza, P., Spear, G. T., Lint, T. F. and Gewurz, H. L-ficolin binding and lectin pathway activation by acetylated low-density lipoprotein. Clin Exp Immunol 151, 275-283 (2008)

Acknowledgements

The CFG is grateful to the following PIs for their contributions to this wiki page: John Hanover

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