Difference between revisions of "Calreticulin"

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This family of GBPs is widespread in evolution and plays a key role in ER quality control<ref name="Ellgaard 2003a">Ellgaard, L. and Frickel, E. M. Calnexin, calreticulin, and ERp57: teammates in glycoprotein folding. Cell Biochem Biophys 39, 223-247 (2003)</ref><ref name="Jorgensen 2003">Jorgensen, M. M., Bross, P. and Gregersen, N. Protein quality control in the endoplasmic reticulum. APMIS Suppl 86-91 (2003)</ref><ref name="Ellgaard 2003">Ellgaard, L. and Helenius, A. Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Biol 4, 181-191 (2003)</ref><ref name="Helenius 2004">Helenius, A. and Aebi, M. Roles of N-linked glycans in the endoplasmic reticulum. Annu Rev Biochem 73, 1019-1049 (2004)</ref><ref>Molinari, M., Eriksson, K. K., Calanca, V., Galli, C., Cresswell, P., Michalak, M. and Helenius, A. Contrasting functions of calreticulin and calnexin in glycoprotein folding and ER quality control. Mol Cell 13, 125-135 (2004)</ref><ref>Deprez, P., Gautschi, M. and Helenius, A. More than one glycan is needed for ER glucosidase II to allow entry of glycoproteins into the calnexin/calreticulin cycle. Mol Cell 19, 183-195 (2005)</ref><ref>Wu, J. C., Liang, Z. Q. and Qin, Z. H. Quality control system of the endoplasmic reticulum and related diseases. Acta Biochim Biophys Sin (Shanghai) 38, 219-226 (2006) </ref><ref>Caramelo, J. J. and Parodi, A. J. Getting in and out from calnexin/calreticulin cycles. J Biol Chem 283, 10221-10225 (2008) </ref><ref name="Michalak 2009">Michalak, M., Groenendyk, J., Szabo, E., Gold, L. I. and Opas, M. Calreticulin, a multi-process calcium-buffering chaperone of the endoplasmic reticulum. Biochem J 417, 651-666 (2009)</ref>. Other ER chaperones have been suggested to have “lectinic” properties including calnexin <ref name="Ellgaard 2003a"/>, but calreticulin is the best studied of this family.
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Calreticulin and calnexin are components of the quality control system that promotes correct folding of proteins that enter the secretory pathway and targets misfolded proteins for degradation. This family of GBPs is widespread in evolution<ref name="Ellgaard 2003a">Ellgaard, L. and Frickel, E. M. Calnexin, calreticulin, and ERp57: teammates in glycoprotein folding. Cell Biochem Biophys 39, 223-247 (2003)</ref><ref name="Jorgensen 2003">Jorgensen, M. M., Bross, P. and Gregersen, N. Protein quality control in the endoplasmic reticulum. APMIS Suppl 86-91 (2003)</ref><ref name="Ellgaard 2003">Ellgaard, L. and Helenius, A. Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Biol 4, 181-191 (2003)</ref><ref name="Helenius 2004">Helenius, A. and Aebi, M. Roles of N-linked glycans in the endoplasmic reticulum. Annu Rev Biochem 73, 1019-1049 (2004)</ref><ref>Molinari, M., Eriksson, K. K., Calanca, V., Galli, C., Cresswell, P., Michalak, M. and Helenius, A. Contrasting functions of calreticulin and calnexin in glycoprotein folding and ER quality control. Mol Cell 13, 125-135 (2004)</ref><ref>Deprez, P., Gautschi, M. and Helenius, A. More than one glycan is needed for ER glucosidase II to allow entry of glycoproteins into the calnexin/calreticulin cycle. Mol Cell 19, 183-195 (2005)</ref><ref>Wu, J. C., Liang, Z. Q. and Qin, Z. H. Quality control system of the endoplasmic reticulum and related diseases. Acta Biochim Biophys Sin (Shanghai) 38, 219-226 (2006) </ref><ref>Caramelo, J. J. and Parodi, A. J. Getting in and out from calnexin/calreticulin cycles. J Biol Chem 283, 10221-10225 (2008) </ref><ref name="Michalak 2009">Michalak, M., Groenendyk, J., Szabo, E., Gold, L. I. and Opas, M. Calreticulin, a multi-process calcium-buffering chaperone of the endoplasmic reticulum. Biochem J 417, 651-666 (2009)</ref>. Other ER chaperones are also glycan-binding proteins<ref name="Ellgaard 2003a"/>, but calreticulin and calnexin are the best studied examples of glycan-binding proteins involved in intracellular glycoprotein quality control.
  
 
== CFG Participating Investigators contributing to the understanding of this paradigm ==
 
== CFG Participating Investigators contributing to the understanding of this paradigm ==

Revision as of 17:42, 17 March 2011

Calreticulin and calnexin are components of the quality control system that promotes correct folding of proteins that enter the secretory pathway and targets misfolded proteins for degradation. This family of GBPs is widespread in evolution[1][2][3][4][5][6][7][8][9]. Other ER chaperones are also glycan-binding proteins[1], but calreticulin and calnexin are the best studied examples of glycan-binding proteins involved in intracellular glycoprotein quality control.

CFG Participating Investigators contributing to the understanding of this paradigm

  • CFG Participating Investigators (PIs) working on calreticulin include: John Hanover, Jamie Rossjohn, Bingdong Sha
  • Non-PIs researchers actively pursuing the ER lectins include: Ari Helenius
  • Non-PIs focused on ER stress include: Mark Lehrman, Kelly Moreman

Progress toward understanding this GBP paradigm

This section documents what is currently known about calreticulin, its carbohydrate ligand(s), and how they interact to mediate cell communication.

Carbohydrate ligands

Ligands for calreticulin are glycoproteins bearing Glc1Man9GlcNAc2.

Cellular expression of GBP and ligands

Calnexin and calreticulin are ubiquitously expressed in the ER of all mammalian cell types.

Biosynthesis of ligands

N-linked glycans generated by the core N-linked biosynthesis pathway (GT Database), are trimmed by the action of ER glucosidases I and II to create the calreticulin ligand Glc1Man9GlcNAc2. The third and final glucose residue is removed by ER glucosidase II, thus destroying the ligand for calreticulin. If the glycoprotein remains incorrectly folded, glucosyltransferase adds back the glucose, regenerating the ligand for calreticulin. Cycles of deglucosylation and re-glucosylation continue until the protein is correctly folded.[10]

Structure

Calreticulin consists of a globular carbohydrate-recognition domain, which has a beta-sandwich fold, and an extended arm, which consists of repeated polypeptide segments that bring unfolded enzymes into proximity with ERp57, a member of the protein disulphide isomerase family, to assist in correct folding. [11] The crystal structure of the carbohydrate-recognition domain with a bound glycan has been determined.[12] The structure of the related protein calnexin has also been determined.[13]

Biological roles of GBP-ligand interaction

Work in a number of laboratories suggests that calreticulin plays a role as a molecular chaperone acting in consort with components of the oligosaccharide processing machinery to ensure ER quality control by limiting the mobility of improperly folded proteins[2][3][4][9][14][15]. Calreticulin has also been suggested to be a component of the peptide loading complex where it interacts with other ER resident proteins to produce class-I major histocompatibility complex (MHC-1) molecules[15][16][17].

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 calreticulin.

Glycan profiling

No data available.

Glycogene microarray

No data available.

Knockout mouse lines

No data available.

Glycan array

Human recombinant calreticulin was screened on the CFG glycan array (click here).

Related GBPs

Calnexin

References

  1. ↑ 1.0 1.1 Ellgaard, L. and Frickel, E. M. Calnexin, calreticulin, and ERp57: teammates in glycoprotein folding. Cell Biochem Biophys 39, 223-247 (2003)
  2. ↑ 2.0 2.1 Jorgensen, M. M., Bross, P. and Gregersen, N. Protein quality control in the endoplasmic reticulum. APMIS Suppl 86-91 (2003)
  3. ↑ 3.0 3.1 Ellgaard, L. and Helenius, A. Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Biol 4, 181-191 (2003)
  4. ↑ 4.0 4.1 Helenius, A. and Aebi, M. Roles of N-linked glycans in the endoplasmic reticulum. Annu Rev Biochem 73, 1019-1049 (2004)
  5. ↑ Molinari, M., Eriksson, K. K., Calanca, V., Galli, C., Cresswell, P., Michalak, M. and Helenius, A. Contrasting functions of calreticulin and calnexin in glycoprotein folding and ER quality control. Mol Cell 13, 125-135 (2004)
  6. ↑ Deprez, P., Gautschi, M. and Helenius, A. More than one glycan is needed for ER glucosidase II to allow entry of glycoproteins into the calnexin/calreticulin cycle. Mol Cell 19, 183-195 (2005)
  7. ↑ Wu, J. C., Liang, Z. Q. and Qin, Z. H. Quality control system of the endoplasmic reticulum and related diseases. Acta Biochim Biophys Sin (Shanghai) 38, 219-226 (2006)
  8. ↑ Caramelo, J. J. and Parodi, A. J. Getting in and out from calnexin/calreticulin cycles. J Biol Chem 283, 10221-10225 (2008)
  9. ↑ 9.0 9.1 Michalak, M., Groenendyk, J., Szabo, E., Gold, L. I. and Opas, M. Calreticulin, a multi-process calcium-buffering chaperone of the endoplasmic reticulum. Biochem J 417, 651-666 (2009)
  10. ↑ Parodi, A.J. (2000) Role of N-oligosaccharides endoplasmic reticulum processing reactions in glycoprotein folding and degradation. Biochem. J., 348, 1-13
  11. ↑ Kato, K. and Kamiya, Y. (2007). Structural views of glycoprotein-fate determination in cells, Glycobiology 17, 1031–1044
  12. ↑ Kozlov, G, Pocanschi, CL, Rosenauer, A, Bastros-Aristizabal, S, Gorelik, Williams, DB and Gehring, K (2010) Structural basis of carbohydrate recognition by calreticulin. Journal of Biological Chemistry 285, 38612-38620
  13. ↑ Schrag, J. D., Bergeron, J. J. M., Li, Y., Borisova, S., Hahn, M., Thomas, D. Y., and Cygler, M.(2001). The structure of calnexin, an ER chaperone involved in quality control of protein folding, Mol. Cell 8, 633–644
  14. ↑ Gelebart, P., Opas, M. and Michalak, M. Calreticulin, a Ca2+-binding chaperone of the endoplasmic reticulum. Int J Biochem Cell Biol 37, 260-266 (2005)
  15. ↑ 15.0 15.1 Wearsch, P. A. and Cresswell, P. The quality control of MHC class I peptide loading. Curr Opin Cell Biol 20, 624-631 (2008)
  16. ↑ Raghavan, M., Del Cid, N., Rizvi, S. M. and Peters, L. R. MHC class I assembly: out and about. Trends Immunol 29, 436-443 (2008)
  17. ↑ Howe, C., Garstka, M., Al-Balushi, M., Ghanem, E., Antoniou, A. N., Fritzsche, S., Jankevicius, G., Kontouli, N., Schneeweiss, C., Williams, A., Elliott, T. and Springer, S. Calreticulin-dependent recycling in the early secretory pathway mediates optimal peptide loading of MHC class I molecules. EMBO J 28, 3730-3744 (2009)

Acknowledgements

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

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