Calcineurin

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Protein phosphatase 3 (formerly 2B), catalytic subunit, alpha isoform

PDB rendering based on 1aui.

Available structures

1aui, 1m63, 1mf8, 1tco, 2jog, 2p6b

Identifiers

Symbols

PPP3CA; CCN1; CNA1; CALN; CALNA; CALNA1; PPP2B

External IDs

OMIM: 114105 MGI: 107164 HomoloGene: 55497 GeneCards: PPP3CA Gene

Gene ontology
Molecular function	• protein serine/threonine phosphatase activity • iron ion binding • calcium ion binding • calmodulin binding • zinc ion binding • hydrolase activity
Cellular component	• nucleus • calcineurin complex • Z disc
Biological process	• G1/S transition of mitotic cell cycle • protein amino acid dephosphorylation • protein import into nucleus • calcium ion transport • response to stress

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 4:
102.16 - 102.49 Mb

Chr 3:
136.61 - 136.87 Mb

PubMed search

[1]

[2]

Calcineurin (CN) is a protein phosphatase also known as protein phosphatase 3, PPP3CA, and formerly known as protein phosphatase 2B (PP2B).^[1] It activates the T cells of the immune system and can be blocked by drugs. Calcineurin activates NFATc (Nuclear Factor of Activated T cell, cytoplasmic), 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 cyclosporin, pimecrolimus and tacrolimus.

1 Mechanism of action
2 Clinical significance
- 2.1 Schizophrenia
- 2.2 Diabetes
3 Interactions
4 References
5 Further reading
6 External links

[edit] 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^[2] 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.

[edit] Clinical significance

[edit] Schizophrenia

Calcineurin is linked to receptors for several brain chemicals including NMDA, dopamine and GABA^[3]. 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.^[4]

[edit] 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.^[5]^[6]

Calcineurin/Nfat signaling is required for perinatal lung maturation and function.^[7]

[edit] Interactions

Calcineurin has been shown to interact with DSCR1^[8] and AKAP5.^[9]

[edit] References

^ "Entrez Gene: PPP3CA protein phosphatase 3 (formerly 2B), catalytic subunit, alpha isoform". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5530.
^ Yamashita M, Katsumata M, Iwashima M, Kimura M, Shimizu C, Kamata T, Shin T, Seki N, Suzuki S, Taniguchi M, Nakayama T (June 2000). "T cell receptor-induced calcineurin activation regulates T helper type 2 cell development by modifying the interleukin 4 receptor signaling complex". J. Exp. Med. 191 (11): 1869–79. doi:10.1084/jem.191.11.1869. PMID 10839803.
^ Bannai, H., Levi, S., Schweizer, C., Inoue, T., Launey, T., Racine, V., et al. (2009). Activity-dependent tuning of inhibitory neurotransmission based on GABAAR diffusion dynamics. Neuron, 62(5), 670-682.
^ Miyakawa T, Leiter LM, Gerber DJ, Gainetdinov RR, Sotnikova TD, Zeng H, Caron MG, Tonegawa S (July 2003). "Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia". Proc. Natl. Acad. Sci. U.S.A. 100 (15): 8987–92. doi:10.1073/pnas.1432926100. PMID 12851457.
^ Heit JJ, Apelqvist AA, Gu X, Winslow MM, Neilson JR, Crabtree GR, Kim SK (September 2006). "Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function". Nature 443 (7109): 345–9. doi:10.1038/nature05097. PMID 16988714.
^ Heit JJ (October 2007). "Calcineurin/NFAT signaling in the beta-cell: From diabetes to new therapeutics". Bioessays 29 (10): 1011–21. doi:10.1002/bies.20644. PMID 17876792.
^ Davé V, Childs T, Xu Y, Ikegami M, Besnard V, Maeda Y, Wert SE, Neilson JR, Crabtree GR, Whitsett JA (October 2006). "Calcineurin/Nfat signaling is required for perinatal lung maturation and function". J. Clin. Invest. 116 (10): 2597–609. doi:10.1172/JCI27331. PMID 16998587.
^ Fuentes, J J; Genescà L, Kingsbury T J, Cunningham K W, Pérez-Riba M, Estivill X, de la Luna S (Jul. 2000). "DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways". Hum. Mol. Genet. (ENGLAND) 9 (11): 1681–90. ISSN 0964-6906. PMID 10861295.
^ Kashishian, A; Howard M, Loh C, Gallatin W M, Hoekstra M F, Lai Y (Oct. 1998). "AKAP79 inhibits calcineurin through a site distinct from the immunophilin-binding region". J. Biol. Chem. (UNITED STATES) 273 (42): 27412–9. ISSN 0021-9258. PMID 9765270.

[edit] 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. PMID 2556704.
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. PMID 2848250.
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. PMID 7593193.
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. PMID 11076863.
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. PMID 11114196.
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.

PDB Gallery

1aui: HUMAN CALCINEURIN HETERODIMER

1m63: Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes

1mf8: Crystal Structure of human calcineurin complexed with cyclosporin A and human cyclophilin

1tco: TERNARY COMPLEX OF A CALCINEURIN A FRAGMENT, CALCINEURIN B, FKBP12 AND THE IMMUNOSUPPRESSANT DRUG FK506 (TACROLIMUS)

2jog: Structure of the calcineurin-NFAT complex

2p6b: Crystal Structure of Human Calcineurin in Complex with PVIVIT Peptide

[edit] External links

MeSH Calcineurin
Calcineurin at eMedicine Dictionary

This hydrolase article is a stub. You can help Wikipedia by expanding it.

Hydrolase: esterases (EC 3.1)

3.1.1: Carboxylic ester hydrolases

Cholinesterase (Acetylcholinesterase, Butyrylcholinesterase) · Pectinesterase · 6-phosphogluconolactonase · PAF acetylhydrolase

Lipase (Bile salt dependent, Gastric/Lingual, Pancreatic, Lysosomal, Hormone-sensitive, Endothelial, Hepatic, Lipoprotein, Monoacylglycerol, Diacylglycerol)

Phospholipase (A1, A2, B)

3.1.2: Thioesterase

Palmitoyl thioesterase · Ubiquitin carboxy-terminal hydrolase L1

3.1.3: Phosphatase

Alkaline phosphatase (ALPI, ALPL, ALPP) · Acid phosphatase (Prostatic)/Tartrate-resistant acid phosphatase/Purple acid phosphatases · Nucleotidase · Glucose 6-phosphatase · Fructose 1,6-bisphosphatase ·

Calcineurin · Phosphoprotein phosphatase (PP2A) · OCRL · Pyruvate dehydrogenase phosphatase · Fructose 6-P,2-kinase:fructose 2,6-bisphosphatase · Protein tyrosine phosphatase · PTEN · Phytase

3.1.4: Phosphodiesterase

Autotaxin · Phospholipase (C, D) · Sphingomyelin phosphodiesterase (1) · PDE1 · PDE2 · PDE3 · PDE4A\PDE4B · PDE5 · Lecithinase (Clostridium perfringens alpha toxin)

3.1.6: Sulfatase

arylsulfatase (Arylsulfatase A, Arylsulfatase B, Arylsulfatase E, Steroid sulfatase) · Galactosamine-6 sulfatase · Iduronate-2-sulfatase · N-acetylglucosamine-6-sulfatase

Nuclease (includes
deoxyribonuclease and
ribonuclease)

3.1.11-16: Exonuclease

Exodeoxyribonuclease	RecBCD

Exoribonuclease	Oligonucleotidase

3.1.21-31: Endonuclease

Endodeoxyribonuclease	Deoxyribonuclease I · Deoxyribonuclease II · Deoxyribonuclease IV · Restriction enzyme · UvrABC endonuclease

Endoribonuclease	RNase III · RNase H (1, 2A, 2B, 2C) · RNase P · RNase A (1, 2, 3, 4/5) · RNase T1 · RNA-induced silencing complex

either deoxy- or ribo-	Aspergillus nuclease S1 · Micrococcal nuclease

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