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)

Like cyclosporin A, cyclolinopeptide A binds specifically bovine cyclophilin A, inhibiting its peptidyl-prolyl cis-trans isomerase activity. We describe here the protein interaction with several synthetic analogues of cyclolinopeptide A, which are either homodetic or disulphide bridged heterodetic cyclopeptides characterized by different ring dimensions, in terms of dissociation and inhibition constants evaluated by fluorescence and inhibition of the enzyme activity, respectively. Dissociation constants from fluorescence experiments are practically identical and about 20-fold lower than for cyclosporin A. On the other hand, inhibition constants differ from compound to compound and are higher than for cyclosporin A. This result is therefore difficult to rationalize, but we would suggest decoupling between binding and inhibitory ability of cyclopeptides. The Pro1 residue of cyclolinopeptide A seems to play a fundamental role in determining the inhibition of the rotamase activity of cyclophilin A, as the homodetic analogue lacking this residue does not show any inhibitory ability. Similarly, heterodetic analogues with a ring size smaller than 7 residues do not display inhibition. We presume that the sequence -Pro-Pro-Phe-Phe- and a ring size of 8 residues for homodetic cyclic peptides could be used as starting points in the targeted synthesis of cyclopeptides able to bind both cyclosporin A and calcineurin. The only peptide showing similar values of the dissociation and inhibition constant is cyclolinopeptide A. This compound can be considered a novel model for the molecular design of immunosuppressant drugs.
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PMID:Specific interaction between bovine cyclophilin A and synthetic analogues of cyclolinopeptide A. 979 8

The effect of immunosuppressant cyclosporin A (CsA) on inward-rectifying K(+)-channels and biochemical analysis have indicated the presence of cyclophilin in guard cells of Vicia faba. In this study, we identified a full-length cDNA sequence, vcCyP, encoding cyclophilin (CyP), a peptidyl-prolyl cis-trans isomerase of guard cell protoplasts (GCPs) from Vicia faba L. The deduced amino acid sequence revealed that vcCyP contained 171 amino acid residues and exhibited a strong similarity to previously described cytosolic CyP isoforms from other plants. vcCyP had seven extra amino acid residues, which is a characteristic of the cytosolic form of plant CyPs. A complex of recombinant vcCyP and CsA inhibited the phosphatase activity of bovine calcineurin, a type 2B protein phosphatase, with a half-inhibitory concentration of 0.2 microM. Protein phosphatase activity was measured in the cytosolic fraction of GCPs using a 32P-labeled myelin basic protein (32P-MBP) and the activity was increased by a physiological concentration of Ca2+ (1 microM). This Ca(2+)-stimulated phosphatase activity was inhibited by CsA, suggesting the presence of both cytosolic CyP and calcineurin-like protein phosphatase in guard cells. Northern blot analysis showed that the transcription level of vcCyP was much higher in GCPs than in root and leaf tissues of Vicia.
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PMID:Characterization of cytosolic cyclophilin from guard cells of Vicia faba L. 1018 2

Cyclophilin B (CyPB), a cyclosporin A (CsA) binding protein, interacts with two types of binding sites at the surface of T-lymphocytes. The type I sites correspond to functional receptors involved in endocytosis and the type II sites to sulfated glycosaminoglycans (GAGs). Mutational analysis of CyPB has revealed that W128, which is part of the CsA-binding pocket, is implicated in the binding to the functional type I receptors and that two amino acid clusters located in the N-terminus ensure the binding to GAGs. The peptidyl-prolyl isomerase activity of CyPB is not required for receptor binding. We have recently demonstrated that CyPB enhances adhesion of peripheral blood T-lymphocytes to fibronectin, a component of the extracellular matrix. We intended to identify additional amino acids involved in the binding of CyPB to its functional type I receptor and to determine regions responsible for the stimulation of peripheral blood T-lymphocyte adhesion. We determined that residues R76, G77, K132, D155, and D158 of the calcineurin (CN) interacting region were implicated in the recognition of type I receptor but not of GAGs. We also found that two different changes in the N-terminal extension that abated binding to GAGs prevented adhesion of peripheral blood T-lymphocytes to coated CyPB, whereas abbrogation of the PPIase activity had no effect. On the other hand, the adhesion of peripheral blood T-lymphocytes to coated fibronectin was not stimulated by CyPB mutants devoid of either type I receptor or GAGs binding activity or by mutants of the PPIase site. Altogether, the results demonstrate that different regions of CyPB are involved in peripheral blood T-lymphocyte activation and imply a novel important physiological function for peptidyl-prolyl isomerase activity.
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PMID:Receptor type I and type II binding regions and the peptidyl-prolyl isomerase site of cyclophilin B are required for enhancement of T-lymphocyte adhesion to fibronectin. 1195 71

Cyclosporin A (CsA) inhibits opening of the mitochondrial permeability transition pore (MPTP), a critical event in some forms of necrotic and apoptotic cell death, by binding to cyclophilin D (CyP-D) and inhibiting its peptidyl-prolyl cis-trans isomerase (PPIase) activity. Sanglifehrin A (SfA), like CsA, exerts its immunosuppressive action by binding to cyclophilin A but at a different site from CsA, and unlike the latter, SfA does not inhibit calcineurin activity. Here we demonstrate that SfA inhibits the PPIase activity of CyP-D (K(0.5) 2 nm) and acts as a potent inhibitor of MPTP opening under both energized and de-energized conditions. However, unlike CsA, the dose-response curve for inhibition by SfA is sigmoidal rather than hyperbolic, suggesting a multimeric structure for the MPTP with cooperativity between subunits. Furthermore, SfA does not prevent CyP-D binding to submitochondrial particles or detergent-solubilized adenine nucleotide translocase (ANT), implying that CyP-D binding to the ANT does not require PPIase activity but pore opening does. Once bound to the MPTP, SfA is not readily dissociated, and inhibition of pore opening is maintained following extensive washing. To investigate the potential of SfA as an inhibitor of cell death in vivo, we used the Langendorff perfused rat heart. SfA caused a time-dependent inhibition of the MPTP that was maintained on mitochondrial isolation to a greater extent than was CsA inhibition. We demonstrate that SfA, like CsA, improves the recovery of left ventricular developed pressure during reperfusion after 30 min of global ischemia and greatly reduces lactate dehydrogenase release, implying inhibition of necrotic damage. Because SfA does not inhibit calcineurin activity, our data suggest that it may be more desirable than CsA for protecting tissues recovering from ischemic episodes and for studying the role of the MPTP in cell death.
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PMID:Sanglifehrin A acts as a potent inhibitor of the mitochondrial permeability transition and reperfusion injury of the heart by binding to cyclophilin-D at a different site from cyclosporin A. 1209 84

FKBP52 is a steroid receptor-associated immunophilin that binds via a tetratricopeptide repeat (TPR) domain to hsp90. FKBP52 has also been shown to interact either directly or indirectly via its peptidylprolyl isomerase (PPIase) domain with cytoplasmic dynein, a motor protein involved in retrograde transport of vesicles toward the nucleus. The functional role for the PPIase domain in receptor movement was demonstrated by showing that expression of the PPIase domain fragment of FKBP52 in 3T3 cells inhibits dexamethasone-dependent nuclear translocation of a green fluorescent protein-glucocorticoid receptor chimera. Here, we show that cytoplasmic dynein is co-immunoadsorbed with two other TPR domain proteins that bind hsp90 (the cyclophilin CyP-40 and the protein phosphatase PP5). Both proteins possess PPIase homology domains, and co-immunoadsorption of cytoplasmic dynein with each is blocked by the PPIase domain fragment of FKBP52. Using purified proteins, we show that FKBP52, PP5, and the PPIase domain fragment bind directly to the intermediate chain of cytoplasmic dynein. PP5 colocalizes with both cytoplasmic dynein and microtubules, and expression of the PPIase domain fragment of FKBP52 in 3T3 cells disrupts its cytoskeletal localization. We conclude that the PPIase domains of the hsp90-binding immunophilins interact directly with cytoplasmic dynein and that this interaction with the motor protein is responsible for the microtubular localization of PP5 in vivo.
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PMID:Binding of hsp90-associated immunophilins to cytoplasmic dynein: direct binding and in vivo evidence that the peptidylprolyl isomerase domain is a dynein interaction domain. 1242 21

FKBP52 is a member of the FK506-binding protein family (FKBPs). The N-terminal domain of FKBP52 (FKBP52-N; residues 1-140) is responsible for peptidyl-prolyl isomerase activity and binding of FK506. Here, the crystal structure of FKBP52-N has been determined by molecular replacement to 2.4 A. FKBP52-N is defined by a six-stranded antiparallel beta-sheet wrapping with a right-handed twist around a short alpha-helix, an architecture similar to that of FKBP12. FKBP52-N is able to bind FK506 in a similar way to FKBP12. The variability in two loop regions (residues 70-76 and 108-127) is the principal reason for the specificity differences between FKBP52-N and FKBP12. The Pro120 change corresponding to Gly89 in FKBP12 limits the conformational adaptation between the loop (residues 108-127) and FK506 and decreases the FK506 affinity, while the Lys121 substitution corresponding to Ile90 of FKBP12 destroys a key interaction between FKBP52-N and calcineurin. It can be inferred from the locations of strictly conserved amino acids in the polypeptide chain that the maintenance of the overall conformation of the PPIase domains of FKBPs is essential for the PPIase activity. The N-terminal region and beta-sheets of FKBP52-N forms a hydrophobic patch which may be responsible for the binding of target proteins such as dynein or PAHX.
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PMID:Structure of the N-terminal domain of human FKBP52. 1249 34

The immunophilin cochaperones, cyclophilin 40 (CyP40), FKBP51 and FKBP52 and PP5, a serine/threonine protein phosphatase, have been implicated as modulators of steroid receptor function through their association with Hsp90, a molecular chaperone with a key role in steroid hormone signalling. Although progress towards a satisfying definition for the role of these components in steroid receptor complexes has been slow, recent developments arising from novel approaches in both yeast and mammalian systems, together with available crystal structures for Hsp90 and some of these cochaperones, are beginning to provide important clues about their function. Hsp90, recently identified as a member of the GHKL superfamily of ATPases, is the central player in receptor assembly, an energy-driven process that allows receptor and the immunophilins to be proximally located, or to interact directly, on a Hsp90 scaffold. Immunophilin structure, relative abundance, their binding affinity for Hsp90 and their ability to interact with specific receptors may all contribute to a selective preference of the immunophilins for individual receptors. Association of receptors with different immunophilins leads to differential functional consequences for receptor activity. Observations of glucocorticoid resistance in New World primates, attributed to FKBP51 overexpression and incorporation into glucocorticoid receptor complexes, have provided the first evidence that these cochaperones can control hormone-binding affinity. Application of a yeast model to FKBP52 function in the glucocorticoid receptor system has now provided crucial evidence that this immunophilin enhances receptor transcriptional activity by increasing receptor avidity for hormone through PPIase-mediated conformational changes in the ligand-binding domain. A recent novel finding suggests that hormone binding may induce a functional exchange of immunophilins in receptor complexes and that the modified complex directs receptor to the nucleus.
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PMID:Immunophilin chaperones in steroid receptor signalling. 1287 Nov 66

Calcineurin is constitutively expressed in bone marrow-derived macrophages. However, macrophage response to macrophage colony-stimulating factor (M-CSF) was not impaired by the use of either calcineurin inhibitors (W-13, chlorpromazine and trifluoperazine), calcium chelators (BAPTA-AM) or Ca2+ channel antagonists (verapamil, nifedipine and diltiazem). Inhibition of calcineurin expression by inhibitory antisense RNA treatment did not result in an inhibition of M-CSF-dependent proliferation. Only very high doses of cyclosporin A and FK506 inhibited macrophage proliferation induced by growth factors, such as M-CSF, granulocyte-macrophage (GM)-CSF or IL-3. This inhibitory action is mediated by the peptidylprolyl isomerase activity of the immunophilins, as demonstrated bythe use of specific inhibitors (rapamycin and sanglifehrin A). These isomerase inhibitors exerted a negative effect on a key element involved in macrophage proliferation, namely the M-CSF-dependent activation of the extracellular signal-regulated kinases (ERK). In summary, the data presented here provide new insights in the mechanism of macrophage proliferation, which may have relevant consequences. First, we showed that in M-CSF-dependent proliferation calcineurin is not involved, and second, that immunophilins play a key role and their activation blocks ERK activation.
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PMID:Macrophage colony-stimulating factor-dependent macrophage proliferation is mediated through a calcineurin-independent but immunophilin-dependent mechanism that mediates the activation of external regulated kinases. 1457 77

Cyclosporin A (CsA) suppresses immune reaction by inhibiting calcineurin activity after forming complex with cyclophilins and is currently widely used as an immunosuppressive drug. Cyclophilin A (CypA) is the most abundantly and ubiquitously expressed family member of cyclophilins. We previously showed that CsA toxicity is mediated by ROS generation as well as by inhibition of peptidyl-prolyl cis-trans isomerase (PPIase) activity of CypA in CsA-treated myoblasts [FASEB J. 16 (2002) 1633]. Since CsA-induced nephrotoxicity is the most significant adverse effect in its clinical utilization, we here investigated the role of CsA inhibition of CypA PPIase activity in its nephrotoxicity using transgenic mouse models. Transgenic mice of either wild type (CypA/wt) or R55A PPIase mutant type (CypA/R55A), a dominant negative mutant of CypA PPIase activity, showed normal growth without any apparent abnormalities. However, CsA-induced nephrotoxicity was virtually suppressed in CypA/wt mice, but exacerbated in CypA/R55A mice, compared to that of littermates. Also, life expectancy was extended in CypA/wt mice and shortened in CypA/R55A mice during CsA administration. Besides, CsA-induced nephrotoxicity was inversely related to the levels of catalase expression and activity. In conclusion, our data provide in vivo evidence that supplement of CypA PPIase activity allows animal's resistance toward CsA-induced nephrotoxicity.
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PMID:Transgenic mice overexpressing cyclophilin A are resistant to cyclosporin A-induced nephrotoxicity via peptidyl-prolyl cis-trans isomerase activity. 1504 94

The immunosuppressive drugs FK506 and rapamycin have anti-malarial properties but their mechanisms of action against malaria parasites remain unknown. The pathway by which these drugs cause immunosuppression in humans is known to involve an FK506-binding protein (FKBP). Homologues of FKBPs have been identified in almost every organism in which they have been sought. Here, we describe the characterisation of the first member of the FKBP family identified in the human malarial parasite, Plasmodium falciparum. This 35-kDa protein, PfFKBP35, comprises a single, N-terminal, FKBP domain and a C-terminal tripartite tetratricopeptide repeat domain. A recombinant form of PfFKBP35, like most other FKBPs, displayed peptidyl-prolyl cis-trans isomerase activity that was inhibitable by FK506 and rapamycin. Unusually the phosphatase activity of calcineurin, the target of the FK506-FKBP complex in T-lymphocytes, was inhibited by PfFKBP35 independently of FK506 binding. PfFKBP35 also inhibited the thermal aggregation in vitro of two model substrates, suggesting that it has general chaperone properties. Analysis of the P. falciparum genome database suggested this to be the only FKBP present in the parasite. The function of this protein remains unknown but the presence of tetratricopeptide repeat motifs suggests a role in intracellular protein transport or modulation of protein function.
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PMID:A Plasmodium falciparum FK506-binding protein (FKBP) with peptidyl-prolyl cis-trans isomerase and chaperone activities. 1566 53


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