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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[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, UDP-glucose:glycoprotein glucosyltransferase adds back the glucose, regenerating the ligand for calreticulin. Cycles of deglucosylation and re-glucosylation continue until the protein is correctly folded.[10]


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

Calreticulin promotes correct folding of secretory glycoprotein. Both calreticulin and calnexin are resident in the ER. Calreticulin possesses a C-terminal ER-retention signal to localize it to the ER lumen, whereas calnexin is anchored to the ER membrane by a transmembrane domain.[2][3][4][9][14][15]. Incorrectly folded glycoproteins are tagged with a single glucose residue that binds to calnexin or calreticulin. The process acts in a cycle, in which glucose is continually removed and then re-attached if the glycoprotein is incorrectly folded.[16][17]

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][18][19]

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

The CFG did not undertake creation of knockout mice for calreticulin because generation of such mice was already underway. The knockout is embryonic lethal, as a result of abnormalities in cardiac development, which may be related to the additional role of calreticulin in controlling Ca2+ levels in cells.[20]

Glycan array

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

Related GBPs



  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. Aebi, M., Bernasconi, R., Clerc, S., and Molinari, M. (2009). N-glycan structures: recognition and processing in the ER. Trends Biochem Sci 35, 74–82
  17. Lederkremer, G.Z. (2009). Glycoprotein folding, quality control and ER-associated degradation. Cur. Opin. Struct. Biol. 19, 515–523
  18. 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)
  19. 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)
  20. Mesaeli, N, Nakamura, K, Zvaritch, E, Dickie, P, Dziak, E, Krause, K-M, Opas, M, MacLennan, DH and Michalak, M. (1999) Calreticulin Is essential for cardiac development. J. Cell Biol. 144, 857-868


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

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