Calcineurin
- 1 February 1999
- journal article
- review article
- Published by Springer Nature in Cell Biochemistry and Biophysics
- Vol. 30 (1) , 115-151
- https://doi.org/10.1007/bf02737887
Abstract
Calcineurin is a serine-threonine specific Ca2+-calmodulin-activated protein phosphatase that is conserved from yeast to humans. Remarkably, this enzyme is the common target for two novel and structurally unrelated immunosuppressive antifungal drugs, cyclosporin A and FK506. Both drugs form complexes with abundant intracellular binding proteins, cyclosporin A with cyclophilin A and FK506 with FKBP 12, which bind to and inhibit calcineurin. The X-ray structure of an FKPB12-FK506-calcineurin AB ternary complex reveals that FKBP12-FK506 binds in a hydophobic groove between the calcineurin A catalytic and the regulatory B subunit, in accord with biochemical and genetic studies on inhibitor action. Calcineurin plays a key role in regulating the transcription factor NF-AT during T-cell activation, and in mediating responses of microorganisms to cation stress. These findings highlight the potential of yeast genetic studies to define novel drug targets and elucidate conserved elements of signal transduction cascades.Keywords
This publication has 148 references indexed in Scilit:
- Overexpression and Purification of Human Calcineurin α fromEscherichia coliand Assessment of Catalytic Functions of Residues Surrounding the Binuclear Metal CenterBiochemistry, 1997
- Role of kinases and the phosphatase calcineurin in the nuclear shuttling of transcription factor NF-AT4Nature, 1996
- Glutamate Induces a Calcineurin‐Mediated Dephosphorylation of Na+,K+‐ATPase that Results in Its Activation in Cerebellar Neurons in CultureJournal of Neurochemistry, 1996
- Myristoylation of Calcineurin B Is Not Required for Function or Interaction with Immunophilin-Immunosuppressant Complexes in the Yeast Saccharomyces cerevisiaePublished by Elsevier ,1995
- The yeast FKS1 gene encodes a novel membrane protein, mutations in which confer FK506 and cyclosporin A hypersensitivity and calcineurin-dependent growthGene, 1994
- Inhibition of calcineurin by cyclosporin A‐cyclophilin requires calcineurin BFEBS Letters, 1992
- Structure and expression of two isoforms of the murine calmodulin-dependent protein phosphatase regulatory subunit (calcineurin B)Biochemical and Biophysical Research Communications, 1992
- The complete primary structure of calcineurin A, a calmodulin binding protein homologous with protein phosphatases 1 and 2ABiochemical and Biophysical Research Communications, 1989
- The refolding of urea-denatured ribonuclease A is catalyzed by peptidyl-prolyl cis-trans isomeraseBiochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, 1985
- A brain protein and its effect on the CA2+-and protein modulator-activated cyclic nucleotide phosphodiesteraseBiochemical and Biophysical Research Communications, 1976