Abstract
Calreticulin is a highly abundant Ca2+-storage protein found in all cells of higher organisms, with the exception of erythrocytes. It is predominantly located in the endoplasmic reticulum where, in tandem with the homologue calnexin, it performs an important role in glycoprotein folding, such as in the assembly of MHC Class I complexes. Under conditions of cellular stress, calreticulin may be released into the extracellular environment, and autoantibodies against the protein have been detected in the sera of a number of autoimmune conditions including patients with systemic lupus erythematosus (SLE) and Sjögren’s syndrome. Although there is currently no crystal structure of calreticulin, the structure of the protein has recently been extensively studied by protein chemistry, circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy. These studies have revealed that the P-domain is an extended, flexible hairpin loop and contains regions of localized secondary structure. Investigation of full length calreticulin has revealed that calreticulin can be classed as an α + β protein, and that it is a highly extended prolate ellipsoid. Cation binding to calreticulin has been demonstrated to modulate both the structure and function of the protein, with Ca2+ and Zn2+ binding increasing the lectin activity and polypeptide binding capacity of calreticulin respectively. Proteolytic digestion of full-length calreticulin has demonstrated a Ca2+-dependent protease-resistant fragment which encompasses the N-terminal half of the molecule. This fragment shows homology to the legume lectin family. The crystal structure of calnexin has now been solved and this has illustrated a more complex domain organization than was originally envisaged for calreticulin and calnexin.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Ostwald T, MacLennan DH. Isolation of a high affinity calcium binding protein from sarcoplasmic reticulum. J Biol Chem 1974; 249:974–979.
Fliegcl L, Burns K, MacLennan DH et al. Molecular cloning of the high affinity calcium-binding protein (calreticulin) of skeletal muscle sarcoplasmic reticulum. J Biol Chem 1989; 264:21522–8.
Smith MJ, Koch GL. Multiple zones in the sequence of calreticulin (CRP55, calregulin, HACBP), a major calcium binding ER/SR protein. Embo J 1989; 8:3581–6.
Baksh S, Michalak M. Expression of calreticulin in Escherichia coli and identification of its Ca2+ binding domains. J Biol Chem 1991; 266:21458–65.
Vassilakos A, Michalak M, Lehrman MA et al. Oligosaccharide binding characteristics of the molecular chaperones calnexin and calreticulin. Biochemistry 1998; 37:3480–90.
Ellgaard L, Riek R, Braun D et al. Three-dimensional structure topology of the calreticulin P-domain based on NMR assignment. FEBS Lett 2001; 488:69–73.
Ellgaard L, Riek R, Herrmann T et al. NMR structure of the calreticulin P-domain. Proc Natl Acad Sci USA 2001; 98:3133–8.
Holaska JM, Black BE, Love DC et al. Calreticulin Is a receptor for nuclear export. J Cell Biol 2001; 152:127–40.
Nakamura K, Zuppini A, Arnaudeau S et al. Functional specialization of calreticulin domains. J Cell Biol 2001; 154:961–72.
Breier A, Michalak M. 2,4,6-Trinitrobenzenesulfonic acid modification of the carboxyl-terminal region (C-domain) of calreticulin. Mol Cell Biochem 1994; 130:19–28.
Pelham HRB. Control of exit from the endoplasmic reticulum. Annu Rev Cell Biol 1989; 5:1–23.
Waisman DM, Salimath BP, Anderson MJ. Isolation and characterization of CAB-63, a novel calcium-binding protein. J Biol Chem 1985; 260:1652–60.
Van PN, Peter F, Soling HD. Four intracisternal calcium-binding glycoproteins from rat liver microsomes with high affinity for calcium. No indication for calsequestrin-like proteins in inositol 1,4,5-trisphosphate-sensitive calcium sequestering rat liver vesicles. J Biol Chem 1989; 264:17494–501.
Matsuoka K, Seta K, Yamakawa Y et al. Covalent structure of bovine brain calreticulin. Biochem J 1994; 298:435–42.
Michalak M, Milner RE, Burns K et al. Calreticulin. Biochem J 1992; 285:681–92. 16. Denning GM, Leidal KG, Holst VA et al. Calreticulin biosynthesis and processing in human myeloid cells: demonstration of signal peptide cleavage and N-glycosylation. Blood 1997; 90:372–81.
Zuber C, Spiro MJ, Guhl B et al. Golgi Apparatus Immunolocalization of Endomannosidase Suggests Post-Endoplasmic reticulum Glucose Trimming: Implications for Quality control. Mol Biol Cell 2000; 11:4227–4240.
Jethmalani SM, Henle KJ, Kaushal GP. Heat shock-induced prompt glycosylation. Identification of P-SG67 as calreticulin. J Biol Chem 1994; 269:23603–9.
Joshi M, Pogue GP, Duncan RC et al. Isolation and characterization of Leishmania donovani calreticulin gene and its conservation of the RNA binding activity. Mol Biochem Parasitol 1996; 81:53–64.
Navazio L, Baldan B, Mariani P et al. Primary structure of the N-linked carbohydrate chains of Calreticulin from spinach leaves. Glycoconj J 1996; 13:977–83.
Peter F, Nguyen Van P, Soling HD. Different sorting of Lys-Asp-Glu-Leu proteins in rat liver. J Biol Chem 1992; 267:10631–7.
Johnson SJ. Characterization of the Structure and Pathophysiological Roles of Human Calreticulin. D. Phil. Thesis 2001.
Hojrup P, Roepstorff P, Houen G. Human placental calreticulin characterization of domain structure and post-translational modifications. Eur J Biochem 2001; 268:2558–65.
Houen G, Koch C. Human placental calreticulin: purification, characterization and association with other proteins. Acta Chem Scand 1994; 48:905–11.
Singh NK, Atreya CD, Nakhasi HL. Identification of calreticulin as a rubella virus RNA binding protein. Proc Natl Acad Sci USA 1994; 91:12770–4.
Cala SE. Determination of a Putative Phosphate-Containing Peptide in Calreticulin. Biochem Biophys Res Commun 1999; 259:233–238.
Corbett EF, Michalak KM, Oikawa K et al. The conformation of calreticulin is influenced by the endoplasmic reticulum luminal environment. J Biol Chem 2000; 275:27177–85.
Corbett EF, Oikawa K, Francois P et al. Ca2+ regulation of interactions between endoplasmic reticulum chaperones. J Biol Chem 1999; 274:6203–11.
Li Z, Stafford WF, Bouvier M. The metal ion binding properties of calreticulin modulate its conformational flexibility and thermal stability. Biochemistry 2001; 40:11193–201.
Manavalan P, Johnson WC Jr. Nature 1983; 305:831–32.
Bouvier M, Stafford WF. Probing the three-dimensional structure of human calreticulin. Biochemistry 2000; 39:14950–9.
Uversky VN. Use of fast protein size-exclusion liquid chromatography to study the unfolding of proteins which denature through the molten globule. Biochemistry 1993; 32:13288–98.
Wu J, Yang JT, Wu C-SC. β-II conformation of all-β proteins can be distinguished from unordered form by circular dichroism. Anal Biochem 1992; 200:359–64.
High S, Lecomte FJ, Russell SJ et al. Glycoprotein folding in the endoplasmic reticulum: a tale of three chaperones? FEBS Lett 2000; 476:38–41.
Frickel EM, Riek R, Jelesarov I et al. TROSY-NMR reveals interaction between ERp57 and the tip of the calreticulin P-domain. Proc Natl Acad Sci USA 2002; 99:1954–9.
Khanna NC, Tokuda M, Waisman DM. Conformational changes induced by binding of divalent cations to calregulin [published erratum appears in J Biol Chem 1986 Dec 5; 261(34): 16279]. J Biol Chem 1986; 261:8883–7.
Saito Y, Lhara Y, Leach MR et al. Calreticulin functions in vitro as a molecular chaperone for both glycosylated and non-glycosylated proteins. Embo J 1999; 18:6718–29.
Peterson JR, Helenius A. In vitro reconstitution of calreticulin-substrate interactions. J Cell Sci 1999; 112:2775–84.
Einspahr H, Parks EH, Sugana K et al. The crystal structure of pea lectin at 3.0-A resolution. J Biol Chem 1986; 261:16518–27.
Emsley J, White HE, O’Hara BP et al. Structure of pentameric human serum amyloid P component. Nature 1994; 367:338–45.
Fiedler K, Simons K. A putative novel class of animal lectins in the secretory pathway homologous to legume lectins (letter). Cell 1994; 77:625–6.
Fiedler K, Simons K. Characterization of VIP36, an animal lectin homologous to leguminous lectins. J Cell Sci 1995; 109:271–6.
Schrag JD, Bergeron JJ, Li Y et al. The Structure of calnexin, an ER chaperone involved in quality control of protein folding. Mol Cell 2001; 8:633–44.
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2003 Springer Science+Business Media New York
About this chapter
Cite this chapter
Johnson, S.J., Håkansson, K.O. (2003). Biochemical and Molecular Properties of Calreticulin. In: Eggleton, P., Michalak, M. (eds) Calreticulin. Molecular Biology Intelligence Unit. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-9258-1_2
Download citation
DOI: https://doi.org/10.1007/978-1-4419-9258-1_2
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-4862-7
Online ISBN: 978-1-4419-9258-1
eBook Packages: Springer Book Archive