Kalcineurin

Kalcineurin (CN) je proteinska fosfataza, takođe poznata kao proteinska fosfataza 3, i kalcijum-zavisna serin-treoninska fosfataza.^[2]. On aktivira T ćelije imunskog sistema, i može se blokirati lekovima. Kalcineurin aktivira nuklearni faktor aktiviranih T ćelija, citoplazmni (NFATc) transkripcioni faktor, putem njegove defosforilacije. Aktivirani NFATc se zatim translocira u jedro, gde povećava izražavanje interleukina 2 (IL-2), koji zatim stimuliše rast i diferencijaciju T ćelijskog responsa. Kalcineurin je biološki cilj klase lekova pod nazivom kalcineurinski inhibitori, koja obuhvata ciklosporin, pimekrolimus i takrolimus.

Kristalografska struktura kalcineurinskog heterodimera formirana od katalitičke (PPP3CA) i regulatorne (PPP3R1) podjedinice.^[1]

Struktura

Kalcineurin je heterodimer od 61-kD kalmodulin-vezujuće katalitičke podjedinice, kalcineurina A i 19-kD Ca²⁺-vezujuće regulatorne podjedinice, kalcineurina B. Postoje tri izozima katalitčke podjedinice, svaka od kojih je kodirana zasebnim genom (PPP3CA, PPP3CB, i PPP3CC) i dve regulatorne izoforme, takođe kodirane zasebnim genima (PPP3R1, PPP3R2).

Proteinska fosfataza 3, katalitička podjedinica, alfa izozim Identifikatori Simbol PPP3CA Alt. simboli CALN, CALNA Entrez 5530 Hugo 9314 OMIM 114105 RefSek NM_000944 UniProt Q08209 Drugi podaci EC broj 3.1.3.16 Lokus Hrom. 4 q24

Proteinska fosfataza 3, katalitička podjedinica, beta izozim Identifikatori Simbol PPP3CB Alt. simboli CALNB Entrez 5532 Hugo 9315 OMIM 114106 RefSek NM_021132 UniProt P16298 Drugi podaci EC broj 3.1.3.16 Lokus Hrom. 10 q22.2

Proteinska fosfataza 3, katalitička podjedinica, gama izozim Identifikatori Simbol PPP3CC Entrez 5533 Hugo 9316 OMIM 114107 RefSek NM_005605 UniProt P48454 Drugi podaci EC broj 3.1.3.16 Lokus Hrom. 8 p21.3

Proteinska fosfataza 3, regulatorna podjedinica B, alfa Identifikatori Simbol PPP3R1 Entrez 5534 Hugo 9317 OMIM 601302 RefSek NM_000945 UniProt P63098 Drugi podaci EC broj 3.1.3.16 Lokus Hrom. 2 p14

Proteinska fosfataza 3, regulatorna podjedinica B, beta Identifikatori Simbol PPP3R2 Entrez 5535 Hugo 9318 OMIM 613821 RefSek NM_147180 UniProt Q96LZ3 Drugi podaci EC broj 3.1.3.16 Lokus Hrom. 9 q31

Reference

1. PDB 1AUI; Kissinger CR, Parge HE, Knighton DR, Lewis CT, Pelletier LA, Tempczyk A, Kalish VJ, Tucker KD, Showalter RE, Moomaw EW (December 1995). „Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex”. Nature 378 (6557): 641–4. DOI:10.1038/378641a0. PMID 8524402.
2. Liu L, Zhang J, Yuan J, Dang Y, Yang C, Chen X, Xu J, Yu L. (March 2005). „Crystal Characterization of a human regulatory subunit of protein phosphatase 3 gene (PPP3RL) expressed specifically in testis”. Mol Biol Rep 32 (1): 41–45. DOI:10.1007/s11033-004-4250-4. PMID 15865209.

Literatura

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Povezano

• Fosfoproteinska fosfataza

Spoljašnje veze

• MeSH Calcineurin
• Calcineurin u rečniku eMedicine