Calreticulin

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Not to be confused with calretinin.
Calreticulin
Protein CALR PDB 1hhn.png
PDB rendering based on 1hhn.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols CALR ; CRT; HEL-S-99n; RO; SSA; cC1qR
External IDs OMIM109091 MGI88252 HomoloGene37911 GeneCards: CALR Gene
RNA expression pattern
PBB GE CALR 200935 at tn.png
PBB GE CALR 212953 x at tn.png
PBB GE CALR 214315 x at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 811 12317
Ensembl ENSG00000179218 ENSMUSG00000003814
UniProt P27797 P14211
RefSeq (mRNA) NM_004343 NM_007591
RefSeq (protein) NP_004334 NP_031617
Location (UCSC) Chr 19:
13.05 – 13.06 Mb
Chr 8:
84.84 – 84.85 Mb
PubMed search [1] [2]

Calreticulin also known as calregulin, CRP55, CaBP3, calsequestrin-like protein, and endoplasmic reticulum resident protein 60 (ERp60) is a protein that in humans is encoded by the CALR gene.[1][2]

Calreticulin is a multifunctional protein that binds Ca2+ ions (a second messenger in signal transduction), rendering it inactive. The Ca2+ is bound with low affinity, but high capacity, and can be released on a signal (see inositol triphosphate). Calreticulin is located in storage compartments associated with the endoplasmic reticulum.[2]

The term "Mobilferrin"[3] is considered to be the same as calreticulin by some sources.[4]

Function[edit]

Calreticulin binds to misfolded proteins and prevents them from being exported from the endoplasmic reticulum to the Golgi apparatus.

A similar quality-control chaperone, calnexin, performs the same service for soluble proteins as does calreticulin. Both proteins, calnexin and calreticulin, have the function of binding to oligosaccharides containing terminal glucose residues, thereby targeting them for degradation. In normal cellular function, trimming of glucose residues off the core oligosaccharide added during N-linked glycosylation is a part of protein processing. If "overseer" enzymes note that residues are misfolded, proteins within the RER will re-add glucose residues so that other calreticulin/calnexin can bind to these proteins and prevent them from proceeding to the Golgi. This leads these aberrantly folded proteins down a path whereby they are targeted for degradation.

Studies on transgenic mice reveal that calreticulin is a cardiac embryonic gene that is essential during development.[5]

Transcription regulation[edit]

Calreticulin is also found in the nucleus, suggesting that it may have a role in transcription regulation. Calreticulin binds to the synthetic peptide KLGFFKR, which is almost identical to an amino acid sequence in the DNA-binding domain of the superfamily of nuclear receptors. The amino terminus of calreticulin interacts with the DNA-binding domain of the glucocorticoid receptor and prevents the receptor from binding to its specific glucocorticoid response element. Calreticulin can inhibit the binding of androgen receptor to its hormone-responsive DNA element and can inhibit androgen receptor and retinoic acid receptor transcriptional activities in vivo, as well as retinoic acid-induced neuronal differentiation. Thus, calreticulin can act as an important modulator of the regulation of gene transcription by nuclear hormone receptors.

Clinical significance[edit]

Calreticulin binds to antibodies in certain sera of systemic lupus and Sjogren patients that contain anti-Ro/SSA antibodies. Systemic lupus erythematosus is associated with increased autoantibody titers against calreticulin, but calreticulin is not a Ro/SS-A antigen. Earlier papers referred to calreticulin as an Ro/SS-A antigen, but this was later disproven. Increased autoantibody titer against human calreticulin is found in infants with complete congenital heart block of both the IgG and IgM classes.[6]

In 2013, two groups detected calreticulin mutations in a majority of JAK2-negative/MPL-negative patients with essential thrombocytosis and primary myelofibrosis, which makes CALR mutations the second most common in myeloproliferative neoplasms. All mutations (insertions or deletions) affected the last exon, generating a reading frame shift of the resulting protein, that creates a novel terminal peptide and causes a loss of endoplasmic reticulum KDEL retention signal. [7][8]

Role in cancer[edit]

Calreticulin (CRT) is expressed in many cancer cells and plays a role to promote macrophages to engulf hazardous cancerous cells. The reason why most of the cells are not destroyed is the presence of another molecule with signal CD47, which blocks CRT. Hence antibodies that block CD47 might be useful as a cancer treatment. In mice models of myeloid leukemia and non-Hodgkin’s lymphoma, anti-CD47 were effective in clearing cancer cells while normal cells were unaffected.[9]

Interactions[edit]

Calreticulin has been shown to interact with Perforin[10] and NK2 homeobox 1.[11]


References[edit]

  1. ^ McCauliffe DP, Zappi E, Lieu TS, Michalak M, Sontheimer RD, Capra JD (July 1990). "A human Ro/SS-A autoantigen is the homologue of calreticulin and is highly homologous with onchocercal RAL-1 antigen and an aplysia "memory molecule"". J. Clin. Invest. 86 (1): 332–5. doi:10.1172/JCI114704. PMC 296725. PMID 2365822. 
  2. ^ a b "Entrez Gene: calreticulin". 
  3. ^ Mobilferrin at the US National Library of Medicine Medical Subject Headings (MeSH)
  4. ^ Beutler E, West C, Gelbart T (1997). "HLA-H and associated proteins in patients with hemochromatosis". Mol. Med. 3 (6): 397–402. PMC 2230203. PMID 9234244. 
  5. ^ Michalak M, Lynch J, Groenendyk J, Guo L, Robert Parker JM, Opas M (November 2002). "Calreticulin in cardiac development and pathology". Biochim. Biophys. Acta 1600 (1–2): 32–7. doi:10.1016/S1570-9639(02)00441-7. PMID 12445456. 
  6. ^ "Entrez Gene: CALR calreticulin". 
  7. ^ Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, Avezov E, Li J, Kollmann K, Kent DG, Aziz A, Godfrey AL, Hinton J, Martincorena I, Van Loo P, Jones AV, Guglielmelli P, Tarpey P, Harding HP, Fitzpatrick JD, Goudie CT, Ortmann CA, Loughran SJ, Raine K, Jones DR, Butler AP, Teague JW, O'Meara S, McLaren S, Bianchi M, Silber Y, Dimitropoulou D, Bloxham D, Mudie L, Maddison M, Robinson B, Keohane C, Maclean C, Hill K, Orchard K, Tauro S, Du MQ, Greaves M, Bowen D, Huntly BJ, Harrison CN, Cross NC, Ron D, Vannucchi AM, Papaemmanuil E, Campbell PJ, Green AR (December 2013). "Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2". N Engl J Med 369 (25): 2391–405. doi:10.1056/NEJMoa1312542. PMID 24325359. 
  8. ^ Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, Them NC, Berg T, Gisslinger B, Pietra D, Chen D, Vladimer GI, Bagienski K, Milanesi C, Casetti IC, Sant'antonio E, Ferretti V, Elena C, Schischlik F, Cleary C, Six M, Schalling M, Schönegger A, Bock C, Malcovati L, Pascutto C, Superti-Furga G, Cazzola M, Kralovics R (December 2013). "Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms". N Engl J Med 369 (25): 2379–90. doi:10.1056/NEJMoa1311347. PMID 24325356. 
  9. ^ Chao MP, Jaiswal S, Weissman-Tsukamoto R, Alizadeh AA, Gentles AJ, Volkmer J, Weiskopf K, Willingham SB, Raveh T, Park CY, Majeti R, Weissman IL (December 2010). "Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47". Sci Transl Med 2 (63): 63ra94. doi:10.1126/scitranslmed.3001375. PMID 21178137. Lay summaryStanford School of Medicine. 
  10. ^ Andrin, C; Pinkoski M J, Burns K, Atkinson E A, Krahenbuhl O, Hudig D, Fraser S A, Winkler U, Tschopp J, Opas M, Bleackley R C, Michalak M (Jul 1998). "Interaction between a Ca2+-binding protein calreticulin and perforin, a component of the cytotoxic T-cell granules". Biochemistry (UNITED STATES) 37 (29): 10386–94. doi:10.1021/bi980595z. ISSN 0006-2960. PMID 9671507. 
  11. ^ Perrone, L; Tell G; Di Lauro R (Feb 1999). "Calreticulin enhances the transcriptional activity of thyroid transcription factor-1 by binding to its homeodomain". J. Biol. Chem. (UNITED STATES) 274 (8): 4640–5. doi:10.1074/jbc.274.8.4640. ISSN 0021-9258. PMID 9988700. 

Further reading[edit]

External links[edit]