Calreticulin

CALR
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3POW, 2CLR, 3DOW, 3POS
Identifiers
Aliases	CALR, CRT, HEL-S-99n, RO, SSA, cC1qR, calreticulin
External IDs	OMIM: 109091; MGI: 88252; HomoloGene: 37911; GeneCards: CALR; OMA:CALR - orthologs
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19p13.13 Start 12,938,578 bp[1] End 12,944,489 bp[1]
Gene location (Mouse) Chr. Chromosome 8 (mouse)[2] Band 8 C3|8 41.21 cM Start 85,568,479 bp[2] End 85,573,563 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in stromal cell of endometrium left lobe of thyroid gland right lobe of thyroid gland islet of Langerhans smooth muscle tissue anterior pituitary epithelium of colon rectum upper lobe of left lung mucosa of transverse colon Top expressed in molar pyloric antrum spermatocyte external carotid artery internal carotid artery epithelium of stomach calvaria spermatid yolk sac cumulus cell More reference expression data BioGPS More reference expression data
Gene ontology Molecular function calcium ion binding protein folding chaperone activity carbohydrate binding hormone binding metal ion binding complement component C1q complex binding mRNA binding iron ion binding unfolded protein binding zinc ion binding integrin binding DNA binding chaperone binding peptide binding androgen receptor binding ubiquitin protein ligase binding RNA binding protein binding Cellular component cytoplasm cytosol endoplasmic reticulum lumen membrane focal adhesion extracellular region perinuclear region of cytoplasm sarcoplasmic reticulum lumen nucleus endocytic vesicle lumen cell surface endoplasmic reticulum extracellular exosome Golgi apparatus intracellular membrane-bounded organelle extracellular matrix intracellular anatomical structure integral component of lumenal side of endoplasmic reticulum membrane sarcoplasmic reticulum smooth endoplasmic reticulum MHC class I peptide loading complex acrosomal vesicle external side of plasma membrane polysome phagocytic vesicle membrane endoplasmic reticulum-Golgi intermediate compartment membrane extracellular space nuclear envelope protein-containing complex endoplasmic reticulum quality control compartment collagen-containing extracellular matrix Biological process negative regulation of neuron differentiation protein folding in endoplasmic reticulum receptor-mediated endocytosis response to organic substance cellular senescence spermatogenesis positive regulation of dendritic cell chemotaxis regulation of apoptotic process cellular response to organic substance positive regulation of phagocytosis negative regulation of intracellular steroid hormone receptor signaling pathway regulation of transcription, DNA-templated negative regulation of retinoic acid receptor signaling pathway cardiac muscle cell differentiation regulation of meiotic nuclear division protein maturation by protein folding positive regulation of cell cycle protein export from nucleus cellular response to lithium ion peptide antigen assembly with MHC class I protein complex antigen processing and presentation of peptide antigen via MHC class I protein stabilization cellular calcium ion homeostasis negative regulation of transcription by RNA polymerase II positive regulation of DNA replication protein folding negative regulation of transcription, DNA-templated cortical actin cytoskeleton organization chaperone-mediated protein folding response to estradiol response to testosterone ATF6-mediated unfolded protein response positive regulation of substrate adhesion-dependent cell spreading sequestering of calcium ion positive regulation of gene expression positive regulation of cell population proliferation protein localization to nucleus glucocorticoid receptor signaling pathway positive regulation of NIK/NF-kappaB signaling antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent negative regulation of translation vesicle fusion with endoplasmic reticulum-Golgi intermediate compartment (ERGIC) membrane positive regulation of endothelial cell migration negative regulation of trophoblast cell migration Sources:Amigo / QuickGO
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: 12.94 – 12.94 Mb Chr 8: 85.57 – 85.57 Mb PubMed search [3] [4]
Wikidata
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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.^[5][6]

Calreticulin is a multifunctional soluble 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 trisphosphate). Calreticulin is located in storage compartments associated with the endoplasmic reticulum and is considered an ER resident protein.^[6]

The term "Mobilferrin"^[7] is considered to be the same as calreticulin by some sources.^[8]

Function

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

A similar quality-control molecular chaperone, calnexin, performs the same service for soluble proteins as does calreticulin, however it is a membrane-bound protein. Both proteins, calnexin and calreticulin, have the function of binding to oligosaccharides containing terminal glucose residues, thereby targeting them for degradation. Calreticulin and Calnexin's ability to bind carbohydrates associates them with the lectin protein family. 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.^[9]

Calreticulin and calnexin are also integral in the production of MHC class I proteins. As newly synthesized MHC class I α-chains enter the endoplasmic reticulum, calnexin binds on to them retaining them in a partly folded state.^[10] After the β2-microglobulin binds to the peptide-loading complex (PLC), calreticulin (along with ERp57) takes over the job of chaperoning the MHC class I protein while the tapasin links the complex to the transporter associated with antigen processing (TAP) complex. This association prepares the MHC class I to bind an antigen for presentation on the cell surface.

Transcription regulation

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

Calreticulin binds to antibodies in certain area of systemic lupus and Sjögren 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.^[11]

In 2013, two groups detected calreticulin mutations in a majority of JAK2-negative/MPL-negative patients with essential thrombocythemia 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.^[12][13]

Role in cancer

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 lymphoma, anti-CD47 were effective in clearing cancer cells while normal cells were unaffected.^[14]

Interactions

Calreticulin has been shown to interact with Perforin^[15] and NK2 homeobox 1.^[16]

References

Further reading

External links

• Calreticulin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)