Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immunosuppressants cyclosporin A and FK506, when complexed with their intracellular receptors, prevent T cell activation by directly binding to the phosphatase calcineurin. We have used molecular modeling and mutagenesis to identify sites on calcineurin important for this interaction. We have created calcineurins that are resistant to both cyclosporin A and FK506 by mutating specific residues in CnB, a calcium-binding protein that regulates the catalytic subunit, CnA. Significantly, on a model of CnB, these mutations map to the latch region, an element of tertiary structure that forms when CnB binds CnA. In addition, we show that this latch region plays an important role in activating the catalytic subunit CnA. These results suggest a molecular mechanism for suppression of calcineurin by cyclosporin A and FK506 involving their binding to the same region of CnB used for allosterically activating CnA.
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PMID:The latch region of calcineurin B is involved in both immunosuppressant-immunophilin complex docking and phosphatase activation. 752 78

The second messenger molecules cAMP and Ca2+ regulate a large number of eukaryotic cellular events. cAMP acts on protein kinases, and Ca2+ works through a ubiquitous calcium-binding protein, calmodulin. The 2 systems are not independent, however, but interact in several important fashions. These interactions can be demonstrated by calmodulin-dependent phosphodiesterase. The bovine heart calmodulin-dependent phosphodiesterase can be phosphorylated by cAMP-dependent protein kinase, resulting in a decrease in the enzyme's affinity for calmodulin. The phosphorylation of calmodulin-dependent phosphodiesterase is blocked by Ca2+ and calmodulin, and reversed by the calmodulin-dependent phosphatase (calcineurin). The dephosphorylation is accompanied by an increase in the affinity of the phosphodiesterase for calmodulin. Results from this study suggest that the activity of this phosphodiesterase is precisely regulated by cross-talk between Ca2+ and cAMP signalling pathways.
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PMID:Molecular interaction between cAMP and calcium in calmodulin-dependent cyclic nucleotide phosphodiesterase system. 798

Calmodulin (CaM), a calcium-binding protein, is present in human tumor tissues and in meningioma. Following a purification procedure using DEAE-cellulose and the polymeric resin 3520, the CaM content of tumor extracts was assayed using CaM-deficient phosphodiesterase (PDE). In the presence of low amounts of the extracts, a concentration dependent stimulation of PDE was observed. However, further addition of higher concentrations of the extract produced a marked inhibition of the CaM stimulation of PDE in 13 of 15 specimens. A wide range (2.44-51.31 units/1 mg tumor [wet weight]) of inhibitor concentration was noted. However, no detectable inhibitory activity of this magnitude was observed in normal human meningeal extracts. The final extracts showed no calcineurin-phosphatase activity in the presence of Ni++, a known activator of this phosphatase. SDS-polyacrylamide gel (10%) electrophoresis of the extracts revealed the typical calmodulin band at 17 kDa plus two additional bands with apparent molecular masses of 21 and 36 kDa respectively. These bands were not seen using normal meningeal extracts.
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PMID:Evidence for a calmodulin inhibitory substance(s) isolated from human meningiomas. 830 44

The crystal structure of the calcium-binding protein calmodulin is used to model the immunologically important calcineurin subunit B. The rough structure is produced by computer-aided homology modeling. Refinement of this using molecular dynamics leads to a suggested structure which appears to satisfy reasonable hydrophilicity and hydrogen-bonding criteria. In the absence of a crystal structure, the model may prove useful in modeling of its interactions with the phosphatase catalytic subunit calcineurin A, and help to explain the calcium modulation of this protein.
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PMID:Tertiary structure of calcineurin B by homology modeling. 838 12

Calcium is known to be of critical importance for hormone secretion in the insulin-producing B-cells of the endocrine, pancreas. Calcium-mediated intracellular signal transduction and the regulation of the concentration of free calcium in B-cells probably involve calcium-binding proteins. In the present study, we have investigated the expression of the calcium/calmodulin-dependent phosphatase, calcineurin, and the EF-hand calcium-binding protein, calretinin, in pancreata of hamsters, gerbils, and rats by immunocytochemistry. Immunocytochemical investigations of serial semithin sections of plastic-embedded pancreata revealed that calcineurin and calretinin were constantly present in islet cells of all three species. In addition to B-cells, these proteins could also be detected in glucagon (A-), somatostatin (D-), and pancreatic polypeptide (PP-) cells. Non-B-cells, especially glucagon-producing A-cells, often exhibited a significantly higher degree of immunoreactivity for both calcium-binding proteins than B-cells. Thus, calcineurin and calretinin may play distinct roles in the regulation of calcium-dependent secretory activities of the different pancreatic endocrine cell types.
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PMID:Rodent pancreatic islet cells contain the calcium-binding proteins calcineurin and calretinin. 927 32

The effect of calcium-binding protein regucalcin on phosphatase activity in the brain cytosol of rats with different ages was investigated. The presence of regucalcin (10(-8) and 10(-7) M) in the enzyme reaction mixture caused a significant increase of neutral p-nitrophenylphosphatase activity in the brain cytosol obtained from 5- and 50-week-old rats. This increase was seen in the absence or presence of calmodulin (2 microg/mL) and calcium chloride (100 microM). Brain cytosolic phosphatase activity was not significantly altered by S-100A (10(-6) M) or calbindin (10(-7) M), which is a calcium-binding protein. Regucalcin-increased phosphatase activity was clearly decreased by N-ethylmaleimide, a modifying reagent of thiol(SH)-group, suggesting that regucalcin acts on the SH-group of the enzyme. Moreover, the presence of anti-regucalcin monoclonal antibody (50-200 ng/mL) in the reaction mixture caused a significant decrease of brain cytosolic phosphatase activity, suggesting that the endogenous regucalcin has a stimulatory effect on the enzyme activity. These results suggest that regucalcin plays a role in the regulation of protein phosphatase in rat brain cytosol.
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PMID:Stimulatory effect of calcium-binding protein regucalcin on phosphatase activity in the brain cytosol of rats with different ages. 967 Dec 64

The ubiquitous calcium-binding protein calmodulin (CaM) has been implicated in the development and function of the nervous system in a variety of eukaryotic organisms. We have generated mutations in the single Drosophila Calmodulin (Cam) gene and examined the effects of these mutations on behavior, synaptic transmission at the larval neuromuscular junction, and structure of the larval motor nerve terminal. Flies hemizygous for Cam3c1, a mutation in the first Ca2+-binding site, exhibit behavioral, neurophysiological, and neuroanatomical abnormalities. In particular, adults exhibit defects in locomotion, coordination, and flight. Larvae exhibit increased neurotransmitter release from the motor nerve terminal at low [Ca2+] in the presence of the K+ channel-blocking drug quinidine. In addition, synaptic bouton structure at motor nerve terminals is altered. These effects are distinct from those produced by altering the activity of the CaM target enzymes CaM-activated kinase II (CaMKII) and CaM-activated adenylyl cyclase (CaMAC). Furthermore, previous in vitro studies of mutant Cam3c1 demonstrated that although its Ca2+ affinity is decreased, Cam3c1 protein can activate CaMKII, CaMAC, and CaM-activated phosphatase calcineurin in a manner similar to wild-type CaM. Thus, the Cam3c1 mutation might affect Ca2+ buffering or interfere with the activation or inhibition of a CaM target distinct from CaMKII or CaMAC.
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PMID:Increased transmitter release and aberrant synapse morphology in a Drosophila calmodulin mutant. 972 45

Calmodulin (CaM) is a 148-residue regulatory calcium-binding protein that activates a wide range of target proteins and enzymes. Calcium-saturated CaM has a bilobal structure, and each domain has an exposed hydrophobic surface region where target proteins are bound. These two "active sites" of calmodulin are remarkably rich in Met residues. Here we have biosynthetically substituted (up to 90% incorporation) the unnatural amino acids ethionine (Eth) and norleucine (Nle) for the nine Met residues of CaM. The substituted proteins bind in a calcium-dependent manner to hydrophobic matrices and a synthetic peptide, encompassing the CaM-binding domain of myosin light-chain kinase (MLCK). Infrared and circular dichroism spectroscopy show that there are essentially no changes in the secondary structure of these proteins compared to wild-type CaM (WT-CaM). One- and two-dimensional NMR studies of the Eth-CaM and Nle-CaM proteins reveal that, while the core of the proteins is relatively unaffected by the substitutions, the two hydrophobic interaction surfaces adjust to accommodate the Eth and Nle residues. Enzyme activation studies with MLCK show that Eth-CaM and Nle-CaM activate the enzyme to 90% of its maximal activity, with little changes in dissociation constant. For calcineurin only 50% activation was obtained, and the K(D) for Nle-CaM also increased 3.5-fold compared with WT-CaM. These data show that the "active site" Met residues of CaM play a distinct role in the activation of different target enzymes, in agreement with site-directed mutagenesis studies of the Met residues of CaM.
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PMID:Substitution of the methionine residues of calmodulin with the unnatural amino acid analogs ethionine and norleucine: biochemical and spectroscopic studies. 1021 Jan 90

Regucalcin was discovered in 1978 as a calcium-binding protein that does not contain EF-hand motif of Ca(2+)-binding domain [M. Yamaguchi and T. Yamamoto, Chem. Pharm. Bull. 26 1915-1918 (1978)]. In recent years, regucalcin has been demonstrated to play an important role as a regulatory protein in Ca2+ signaling in rat liver and kidney cells. The organization of the rat regucalcin gene consists of seven exons and six introns. The mRNA is mainly present in liver and kidney with a size of 1.8 kb. Hepatic regucalcin mRNA expression has been shown to be stimulated by various factors including calcium, calcitonin, insulin, and estrogen in rats. The mRNA is also expressed in hepatoma cells (Morris hepatoma, HepG2, and rat hepatoma H4-II-E cells). Regucalcin plays a role in the maintenance of intracellular Ca2+ homeostasis due to activating Ca2+ pump enzymes in the plasma membrane (basolateral membrane) and microsomes of liver and renal cortex cells. Moreover, regucalcin has an inhibitory effect on the activation of Ca2+/calmodulin-dependent enzymes and protein kinase C. Also, regucalcin has been demonstrated to regulate nuclear function in liver cells; it can inhibit Ca(2+)-activated DNA fragmentation, DNA and RNA synthesis, protein kinase and protein phosphatase activities in the nuclei. Such an effect is also seen in the nuclei of regenerating rat liver. Regucalcin may play a physiological role in the control for overexpression of proliferative cells. Regucalcin has been proposed to be an important regulatory protein in Ca2+ signaling system, and it plays a multifunctional role in liver and kidney cells.
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PMID:Role of regucalcin in calcium signaling. 1080 75

Calcineurin, protein phosphatase 2B, is a calcium-binding protein that has been shown to modulate NMDA receptor activity (Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. Nature 369 (1994) 235; Regulation of glycine-insensitive desensitisation of the NMDA receptor in outside-out patches. J. Neurophysiol. 71 (1994) 754; Calcineurin acts via the C-terminus of NR2A to modulate desensitization of NMDA receptors. Neuropharmacology 42 (2002) 593) and synaptic transmission (Synaptic desensitization of NMDA receptors by calcineurin. Science 267 (1995) 1510; beta-adrenergic regulation of synaptic NMDA receptors by cAMP-dependent protein kinase. Neuron 16 (1996) 415). Calmodulin, a necessary co-factor for calcineurin (Calmodulin binding by calcineurin. J. Biol. Chem. 262 (1987) 15062), has also been shown to inhibit NMDA receptor activity (Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Cell 84 (1996) 745; Direct effects of calmodulin on NMDA receptor single-channel gating in rat hippocampal granule cells. J. Neurosci. 22 (2002) 8860) in a calcium dependent manner (Calmodulin mediates calcium-dependent inactivation of N-methyl-d-aspartate receptors. Neuron 21 (1998) 443; Interactions of calmodulin and alpha-actinin with the NR1 subunit modulate calcium-dependent inactivation of NMDA receptors. J. Neurosci. 19 (1999) 1165). In order to gain insight into the likely actions and interactions of calcineurin and calmodulin at excitatory synapses, we have investigated the effects of these two proteins on single NMDA receptor channel activity. Calcineurin and calmodulin are both known to reduce channel open time (Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. Nature 369 (1994) 235; Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Cell 84 (1996) 745), and the duration of receptor activations or superclusters. They are, therefore, predicted to shorten the synaptic current decay (Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. Nature 369 (1994) 235; Direct effects of calmodulin on NMDA receptor single-channel gating in rat hippocampal granule cells. J. Neurosci. 22 (2002) 8860). In agreement with Lieberman and Mody (Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. Nature 369 (1994) 235), the results of this study indicate calcineurin plus calmodulin reduces channel open time. However, this effect is not as pronounced as that observed in the presence of calmodulin alone. Calcineurin plus calmodulin was also found to increase single channel shut time. We conclude that in addition to its direct effects on single channel activity, calcineurin regulates the effects of calmodulin on NMDA receptor activity.
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PMID:Inhibitory interactions of calcineurin (phosphatase 2B) and calmodulin on rat hippocampal NMDA receptors. 1538 Mar 69


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