Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immunosuppressants rapamycin and FK506 bind to the same intracellular protein, the immunophilin FKBP12. The FKB12-FK506 complex interacts with and inhibits the Ca(2+)-activated protein phosphatase calcineurin. The target of the FKBP12-rapamycin complex has not yet been identified. We report that a protein complex containing 245 kDa and 35 kDa components, designated rapamycin and FKBP12 targets 1 and 2 (RAFT1 and RAFT2), interacts with FKBP12 in a rapamycin-dependent manner. Sequences (330 amino acids total) of tryptic peptides derived from the 245 kDa RAFT1 reveal striking homologies to the yeast TOR gene products, which were originally identified by mutations that confer rapamycin resistance in yeast. A RAFT1 cDNA was obtained and found to encode a 289 kDa protein (2549 amino acids) that is 43% and 39% identical to TOR2 and TOR1, respectively. We propose that RAFT1 is the direct target of FKBP12-rapamycin and a mammalian homolog of the TOR proteins.
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PMID:RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. 751 56

The immunosuppressant FK-506 (tacrolimus) forms a complex with a ubiquitous intracellular receptor, FK-506 binding protein (FKBP12), and this complex inhibits the heterodimeric Ca2+/calmodulin-dependent phosphatase, calcineurin, an essential component of the T-cell receptor signal transduction pathway. Using a series of truncated calcineurin catalytic subunits, we show here that a region within the catalytic subunit that regulates phosphatase activity, the autoinhibitory domain, also regulates the Ca(2+)-dependent interaction of calcineurin with the FK-506.FKBP12 complex. Deletion of this domain produces constitutive activation of the phosphatase as demonstrated by transient transfection experiments in which expression of the truncated protein permitted Ca(2+)-independent induction of interleukin-2 transcription. Thus, deletion of the autoinhibitory domain is necessary and sufficient to constitutively activate calcineurin (CaN). Furthermore, CaN A467-492, an inhibitory peptide based on the autoinhibitory domain from calcineurin (ITSFEEAKGLDRINERMPPRRDAMP), inhibited dephosphorylation of the RII peptide substrate competitively with a Ki = 4 microM, consistent with binding of the autoinhibitory domain at the active site of the enzyme. To assess the role of the autoinhibitory domain in regulating the interaction of CaN with the FK-506.FKBP12 complex, we reconstituted wild type and mutant phosphatase heterodimers using in vitro transcribed and translated subunits. Association of the reconstituted calcineurin heterodimers with FKBP12 was dependent on FK-506. In the case of the wild type heterodimer, association with the FK-506.FKBP12 complex was also dependent upon Ca2+; however, mutant catalytic subunits, in which the autoinhibitory domains were deleted, associated with the drug-binding protein complex in the presence of 10 mM EGTA. These results indicate that the conserved autoinhibitory domain regulates both Ca(2+)-dependent phosphatase activity and association with the FK-506.FKBP12 complex.
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PMID:Regulation of calcineurin phosphatase activity and interaction with the FK-506.FK-506 binding protein complex. 751 61

Tacrolimus(FK506) is a strong immuno-suppressant and shows its activity through inhibiting IL-2 mRNA transcription by forming pentameric complex with intracellular receptor(FK506 binding protein 12 kDa or FKBP12), Ca2+, calmodulin, and calcineurin. Here, we report the binding activity to FKBP12, the pentameric complex formation and Con-A response inhibiting activities of 7 metabolites. C15-demethylated metabolite(M-3) needed higher quantity to compete in Con-A assay and in pentamer formation assay, although it binds more strongly to FKBP12. The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to FKBP12, but a single step reaction by components for the pentamer formation.
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PMID:Interaction of tacrolimus(FK506) and its metabolites with FKBP and calcineurin. 751 78

FK-506, a potent immunosuppressive drug, acts during the commitment phase of T-lymphocyte activation to block a subset of calcium-associated events necessary for transcription of certain early lymphokine genes. The drug binds to an abundant, cytosolic 11.8-kDa protein termed the FK-506-binding protein (FKBP12). The FKBP12.FK-506 complex inhibits calcineurin, a calcium-dependent phosphatase that is a component of the signal transduction pathway leading to early lymphokine gene transcription. FKBP12 is one member of a growing gene family. Prior to this report, all other FKBP family members had been irrelevant to the mechanism of action of FK-506 because no other FKBP.FK-506 complexes were able to bind and inhibit calcineurin. Here, we report the purification and characterization of a novel FK-506-binding protein, FKBP12.6. Having 85% amino acid sequence identity to FKBP12, FKBP12.6 is, among the FKBPs, most closely related to FKBP12. When complexed with FK-506, FKBP12.6 binds to and inhibits calcineurin, making it only the second FKBP discovered thus far to do so. The ability to inhibit calcineurin establishes the potential relevance of FKBP12.6 to the immunosuppressive or toxic side effects of FK-506.
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PMID:Inhibition of calcineurin by a novel FK-506-binding protein. 752 Apr 38

The immunosuppressive peptide cyclosporin A inhibits the growth of malaria parasites in vitro and in vivo, but little is known about its mechanism of antimalarial action. The immunosuppressive action of cyclosporin A is believed to result from binding of the drug to cyclophilins (intracellular peptidyl-prolyl cis-trans isomerases), and inhibition of the protein phosphatase calcineurin by the cyclosporin A-cyclophilin complex. Two immunosuppressive macrolides, FK506 and rapamycin, bind to a distinct isomerase, FKBP12, and the FK506-FKBP complex also inhibits calcineurin. Calcineurin itself is apparently involved in signal transduction between the T-cell membrane and nucleus, and its inhibition blocks T-cell activation. Rapamycin inhibits a later step in T-cell proliferation. Peptidyl-propyl cis-trans isomerase activity was detected in extracts of Plasmodium falciparum. It was completely inhibited by concentrations of cyclosporin A above 0.1 microM, but not by FK506 or rapamycin, and probably represented one or more cyclophilins. Comparison of the antimalarial and anti-isomerase activities of a series of cyclosporin analogues failed to reveal a correlation between the two properties. Cyclosporin A and its more active 8'-oxymethyl-dihydro-derivative, in combination with the cyclophilin-containing P. falciparum extract, inhibited the protein phosphatase activity of bovine calcineurin. Therefore inhibition of a putative P. falciparum calcineurin by a complex of CsA and cyclophilin might be responsible for the antimalarial action of the drug. The most active cyclosporin, however, was a 3'-keto-derivative of cyclosporin D (SDZ PSC-833) which inhibited P. falciparum growth with a 50% inhibitory concentration (IC50) of 0.032 microM (compared with 0.30 microM for cyclosporin A), but was a poor inhibitor of the parasite isomerase. 3'-Keto-cyclosporin D has negligible immunosuppressive activity, but it strongly inhibits the P-glycoprotein of multi-drug resistant mammalian tumour cells. FK506 and rapamycin were also active antimalarials (IC50 of 1.9 and 2.6 microM, respectively) but in the absence of detectable FKBP in P. falciparum extracts, their mechanisms of antimalarial action remain unclear.
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PMID:Roles of peptidyl-prolyl cis-trans isomerase and calcineurin in the mechanisms of antimalarial action of cyclosporin A, FK506, and rapamycin. 752 Jun 96

The nontransformed steroid receptors contain several non-steroid binding proteins, such as hsp90, hsp70, and p59. Recently, we and others have shown that p59 (FKBP59) is an immunophilin which binds two potent immunosuppressants, FK506 and rapamycin. This raises the possibility that FK506 or rapamycin may modify the function of steroid receptors. To develop this line of inquiry, we chose a yeast model system in which the human progesterone receptor form B (hPR-B) was cotransformed with a reporter gene. The reporter contains two copies of a progesterone response element/glucocorticoid response element (PRE/GRE) upstream of the CYC1 promoter which are linked to the lacZ gene of Escherichia coli. We found that FK506 potentiated the ability of progesterone in activating transcription. To gain insight into the mechanism of FK506's regulation of PR action, we questioned whether calcineurin is involved, because it has been shown that FK506 is a specific inhibitor of calcineurin, a Ca(2+)- and calmodulin-regulated phosphatase, through the formation of an FKBP12-FK506-calcineurin-calmodulin complex. We found that 15-O-desmethyl-FK520, an FK506 analogue which is an excellent ligand of FKBP12, but a poor inhibitor of calcineurin, failed to induce the same effect as FK506. We also found that calmidazolium, a calmodulin antagonist, mimicked FK506's action. Furthermore, immunoblot analysis showed that both FK506 and calmidazolium potentiated the effect of progesterone in decreasing the mobility of hPR-B upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). This suggests that FK506 and calmidazolium may cooperate with progesterone in increasing the level of hPR-B phosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Potentiation of progesterone receptor-mediated transcription by the immunosuppressant FK506. 752 Dec 10

The immunosuppressive action of the drug FK506 involves inhibition of calcineurin in T-lymphocytes by a complex of FK506 and an FK506 binding protein, FKBP12, a member of the immunophilin protein family. The functional role of brain immunophilins is, however, unclear. We show here that FK506 is a powerful neuroprotective agent in an in vivo model of focal cerebral ischaemia when administered up to 60 min post-occlusion. The minimum effective neuroprotective dose is comparable with the immunosuppressant dose in humans, suggesting that FK506 may have clinical potential for the treatment of stroke. Although the related immunosuppressants rapamycin and cyclosporin failed to reduce brain damage, the finding that rapamycin pretreatment blocked the effect of FK506 confirms a role for immunophilins in the neuroprotective mechanism.
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PMID:Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischaemia. 752 3

The effect of recombinant FKBP-59/HBI or of its first N-terminal domain FKBP-59/HBI-I on the phosphatase activity of calcineurin (a Ca(+2)-calmodulin dependent phosphatase) was tested in vitro in the presence or absence of the immunosuppressant drug FK506. Contrarily to the inhibition observed with the immunosuppressant complex FKBP-12-FK506, no significant inhibition was observed with FKBP-59/HBI or FKBP-59/HBI-I in the presence of FK506, even though FKBP-59/HBI-1 is nearly 55% homologous to the immunophilin FKBP-12. Inhibition was tested both with native calcineurin (calcineurin A: Mr 58-59 kDa) and with protease activated, calmodulin independent calcineurin (calcineurin A: Mr 45 kDa). There was no competitive effect of FKBP-59 on the inhibitory activity of the FKBP-12-FK506 complex, even when the molar concentration of FKBP-59/HBI was 100 times higher than that of FKBP-12. Clearly, although the first domain of FKBP-59/HBI displays several structural and functional features of FKBP-12, it does not interact with calcineurin.
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PMID:Rabbit FKBP-59/HBI does not inhibit calcineurin activity in vitro. 752 47

The binding of the FK506/FKBP-12 complex to calcineurin (CN), its putative target for immunosuppression, involves recognition of solvent-exposed regions of the ligand as well as FKBP-12 residues near the active site. The R42K, H87V double mutation of FKBP-12 decreases the CN affinity of the complex by 550-fold [Aldape, R. A., Futer, O., DeCenzo, M. T., Jarrett, B. P., Murcko, M. A., & Livingston, D. J. (1992) J. Biol. Chem. 267, 16029-16032]. This work reports the solution structure of 13C-labeled FK506 bound to R42K, H87V FKBP-12. Assignments and NOE measurements at three mixing times were made from inverse-detected 1H-13C NMR experiments. Structures were calculated by several different methods, including distance geometry, restrained molecular dynamics, and molecular dynamics with time-averaged restraints. The NMR structures of the ligand are very well defined by the NOE restraints and differ slightly from the X-ray structure in regions that are involved in crystal packing. Comparison with the NMR structure of FK506 bound to wild-type FKBP-12 reveals that the R42K, H87V mutation causes the ligand backbone near C16 to move by 2.5 to 4.5 A, reorients 15-MeO by 90 degrees, and shifts 13-MeO by approximately 1.5 A. FK506 appears to undergo a concerted, mutationally induced shift in the binding pocket, with the greatest changes occurring in the effector region of the drug. The altered effector conformation of mutant-bound FK506 may perturb interactions between the drug and CN, thus accounting for the effect of the double mutation upon the CN inhibitory activity of the complex.
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PMID:Solution structure of FK506 bound to the R42K, H87V double mutant of FKBP-12. 752 62

Specificity of protein kinases and phosphatases may be achieved through compartmentalization with preferred substrates. In neurons, adenosine 3', 5'-monophosphate (cAMP)-dependent protein kinase (PKA) is localized at postsynaptic densities by association of its regulatory subunit with an A kinase anchor protein, AKAP79. Interaction cloning experiments demonstrated that AKAP79 also binds protein phosphatase 2B, or calcineurin (CaN). A ternary complex of PKA, AKAP, and CaN was isolated from bovine brain, and colocalization of the kinase and the phosphatase was established in neurites of cultured hippocampal neurons. The putative CaN-binding domain of AKAP79 is similar to that of the immunophilin FKBP-12, and AKAP79 inhibited CaN phosphatase activity. These results suggest that both PKA and CaN are targeted to subcellular sites by association with a common anchor protein and thereby regulate the phosphorylation state of key neuronal substrates.
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PMID:Association of protein kinase A and protein phosphatase 2B with a common anchoring protein. 752 41


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