Calcineurin

Crystallographic structure of calcineurin heterodimer composed of the catalytic (PPP3CA and regulatory (PPP3R1) subunits.

Calcineurin (CN) is a protein phosphatase also known as protein phosphatase 3, and calcium-dependent serine-threonine phosphatase. It activates the T cells of the immune system and can be blocked by drugs. Calcineurin activates nuclear factor of activated T cell, cytoplasmic (NFATc), a transcription factor, by dephosphorylating it. The activated NFATc is then translocated into the nucleus, where it upregulates the expression of interleukin 2 (IL-2), which, in turn, stimulates the growth and differentiation of T cell response. Calcineurin is the target of a class of drugs called calcineurin inhibitors, which includes cyclosporine, pimecrolimus and tacrolimus.

Structure

Calcineurin is a heterodimer of a 61-kD calmodulin-binding catalytic subunit, calcineurin A and a 19-kD Ca²⁺-binding regulatory subunit, calcineurin B. There are three isozymes of the catalytic subunit, each encoded by a separate gene (PPP3CA, PPP3CB, and PPP3CC) and two isoforms of the regulatory, also encoded by separate genes (PPP3R1, PPP3R2).

protein phosphatase 3, catalytic subunit, alpha isozyme Identifiers Symbol PPP3CA Alt. symbols CALN, CALNA Entrez 5530 HUGO 9314 OMIM 114105 RefSeq NM_000944 UniProt Q08209 Other data EC number 3.1.3.16 Locus Chr. 4 q24

protein phosphatase 3, catalytic subunit, beta isozyme Identifiers Symbol PPP3CB Alt. symbols CALNB Entrez 5532 HUGO 9315 OMIM 114106 RefSeq NM_021132 UniProt P16298 Other data EC number 3.1.3.16 Locus Chr. 10 q22.2

protein phosphatase 3, catalytic subunit, gamma isozyme Identifiers Symbol PPP3CC Entrez 5533 HUGO 9316 OMIM 114107 RefSeq NM_005605 UniProt P48454 Other data EC number 3.1.3.16 Locus Chr. 8 p21.3

protein phosphatase 3, regulatory subunit B, alpha Identifiers Symbol PPP3R1 Entrez 5534 HUGO 9317 OMIM 601302 RefSeq NM_000945 UniProt P63098 Other data EC number 3.1.3.16 Locus Chr. 2 p14

protein phosphatase 3, regulatory subunit B, beta Identifiers Symbol PPP3R2 Entrez 5535 HUGO 9318 OMIM 613821 RefSeq NM_147180 UniProt Q96LZ3 Other data EC number 3.1.3.16 Locus Chr. 9 q31

Mechanism of action

When an antigen-presenting cell interacts with a T cell receptor on T cells, there is an increase in the cytoplasmic level of calcium, which activates calcineurin, by binding a regulatory subunit and activating calmodulin binding. Calcineurin induces different transcription factors (NFATs) that are important in the transcription of IL-2 genes. IL-2 activates T-helper lymphocytes and induces the production of other cytokines. In this way, it governs the action of cytotoxic lymphocytes and NK cells. The amount of IL-2 being produced by the T-helper cells is believed to influence the extent of the immune response significantly.

Clinical significance

Schizophrenia

Calcineurin is linked to receptors for several brain chemicals including NMDA, dopamine and GABA. An experiment with genetically-altered mice that could not produce calcineurin showed similar symptoms as in humans with schizophrenia: impairment in working memory, attention deficits, aberrant social behavior, and several other abnormalities characteristic of schizophrenia.

Diabetes

Scientists believe that calcineurin might prove to be one of the two keys, along with NFAT, in improving the function of diabetics' pancreatic beta cells.

Calcineurin/Nfat signaling is required for perinatal lung maturation and function.

Interactions

Calcineurin has been shown to interact with DSCR1 and AKAP5.

Further reading

• Crabtree GR (1999). "Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT". Cell 96 (5): 611–4. doi:10.1016/S0092-8674(00)80571-1. PMID 10089876. 
• Giri PR, Higuchi S, Kincaid RL (1992). "Chromosomal mapping of the human genes for the calmodulin-dependent protein phosphatase (calcineurin) catalytic subunit". Biochem. Biophys. Res. Commun. 181 (1): 252–8. doi:10.1016/S0006-291X(05)81410-X. PMID 1659808. 
• Kincaid RL, Giri PR, Higuchi S, et al. (1990). "Cloning and characterization of molecular isoforms of the catalytic subunit of calcineurin using nonisotopic methods". J. Biol. Chem. 265 (19): 11312–9. PMID 2162844. 
• Guerini D, Klee CB (1990). "Cloning of human calcineurin A: evidence for two isozymes and identification of a polyproline structural domain". Proc. Natl. Acad. Sci. U.S.A. 86 (23): 9183–7. doi:10.1073/pnas.86.23.9183. PMC 298458. PMID 2556704. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=298458. 
• Kincaid RL, Nightingale MS, Martin BM (1988). "Characterization of a cDNA clone encoding the calmodulin-binding domain of mouse brain calcineurin". Proc. Natl. Acad. Sci. U.S.A. 85 (23): 8983–7. doi:10.1073/pnas.85.23.8983. PMC 282646. PMID 2848250. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=282646. 
• Coghlan VM, Perrino BA, Howard M, et al. (1995). "Association of protein kinase A and protein phosphatase 2B with a common anchoring protein". Science 267 (5194): 108–11. doi:10.1126/science.7528941. PMID 7528941. 
• Griffith JP, Kim JL, Kim EE, et al. (1995). "X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex". Cell 82 (3): 507–22. doi:10.1016/0092-8674(95)90439-5. PMID 7543369. 
• Shibasaki F, McKeon F (1995). "Calcineurin functions in Ca(2+)-activated cell death in mammalian cells". J. Cell Biol. 131 (3): 735–43. doi:10.1083/jcb.131.3.735. PMC 2120616. PMID 7593193. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2120616. 
• Muramatsu T, Kincaid RL (1993). "Molecular cloning of a full-length cDNA encoding the catalytic subunit of human calmodulin-dependent protein phosphatase (calcineurin A alpha)". Biochim. Biophys. Acta 1178 (1): 117–20. doi:10.1016/0167-4889(93)90117-8. PMID 8392375. 
• Cameron AM, Steiner JP, Roskams AJ, et al. (1996). "Calcineurin associated with the inositol 1,4,5-trisphosphate receptor-FKBP12 complex modulates Ca2+ flux". Cell 83 (3): 463–72. doi:10.1016/0092-8674(95)90124-8. PMID 8521476. 
• Kissinger CR, Parge HE, Knighton DR, et al. (1996). "Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex". Nature 378 (6557): 641–4. doi:10.1038/378641a0. PMID 8524402. 
• Wang MG, Yi H, Guerini D, et al. (1997). "Calcineurin A alpha (PPP3CA), calcineurin A beta (PPP3CB) and calcineurin B (PPP3R1) are located on human chromosomes 4, 10q21→q22 and 2p16→p15 respectively". Cytogenet. Cell Genet. 72 (2–3): 236–41. doi:10.1159/000134198. PMID 8978785. 
• Shibasaki F, Kondo E, Akagi T, McKeon F (1997). "Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and Bcl-2". Nature 386 (6626): 728–31. doi:10.1038/386728a0. PMID 9109491. 
• Kashishian A, Howard M, Loh C, et al. (1998). "AKAP79 inhibits calcineurin through a site distinct from the immunophilin-binding region". J. Biol. Chem. 273 (42): 27412–9. doi:10.1074/jbc.273.42.27412. PMID 9765270. 
• Wang HG, Pathan N, Ethell IM, et al. (1999). "Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD". Science 284 (5412): 339–43. doi:10.1126/science.284.5412.339. PMID 10195903. 
• Fuentes JJ, Genescà L, Kingsbury TJ, et al. (2000). "DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways". Hum. Mol. Genet. 9 (11): 1681–90. doi:10.1093/hmg/9.11.1681. PMID 10861295. 
• Hartley JL, Temple GF, Brasch MA (2001). "DNA Cloning Using In Vitro Site-Specific Recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=310948. 
• Frey N, Richardson JA, Olson EN (2001). "Calsarcins, a novel family of sarcomeric calcineurin-binding proteins". Proc. Natl. Acad. Sci. U.S.A. 97 (26): 14632–7. doi:10.1073/pnas.260501097. PMC 18970. PMID 11114196. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=18970. 
• Siddiq A, Miyazaki T, Takagishi Y, et al. (2001). "Expression of ZAKI-4 messenger ribonucleic acid in the brain during rat development and the effect of hypothyroidism". Endocrinology 142 (5): 1752–9. doi:10.1210/en.142.5.1752. PMID 11316738. 

External links

• MeSH Calcineurin
• Calcineurin at eMedicine Dictionary