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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many neurohormones alter the force of cardiac contraction by variations in the intracellular Ca2+ concentration. alpha 1-Adrenergic and muscarinic stimulations, rather, modify the sensitivity of contractile proteins to Ca(2+)-calmodulin-myosin light-chain kinase (MLCK) complex induces a large increase in Ca2+ sensitivity (0.14 pCa unit) of these easily accessible myofilaments. This increase is further enhanced by up to 0.19 pCa unit when protein kinase C (PKC) is added together with MLCK. Similarly, the Ca2+ ATPase activity of skinned cells in suspension is increased in the presence of MLCK and further in the presence of both kinases. 32P-labelling and SDS/PAGE show that these changes are associated with light-chain 2 (LC2) phosphorylation together with phosphorylation of troponin I and troponin T when PKC is added. Although to a smaller extent than in smooth muscle, phosphorylation of cardiac myosin LC2 may be involved in the modulation of heart contractility.
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PMID:Protein kinase C enhances myosin light-chain kinase effects on force development and ATPase activity in rat single skinned cardiac cells. 138 18

A Ca(2+)-dependent ATPase, purified from cardiac microsomal membranes by solubilization and chromatography, is identified as cardiac sarcoplasmic reticulum ATPase on the basis of its electrophoretic mobility and its trypsin digestion pattern. The ATPase (both in membranous and purified form) is stimulated by calmodulin, while the skeletal muscle ATPase is not. Rapid kinetic experiments demonstrate that the calmodulin stimulation is already present within the first enzyme cycle following the addition of ATP, and consists of an increased turnover of the phosphorylated enzyme intermediate. The calmodulin effect does not involve the phosphorylation of any protein other than the ATPase. Following the incubation of ATPase with [gamma-32P]ATP, even in conditions of calmodulin stimulation, radioactive phosphorus is found only on the ATPase electrophoretic band, corresponding to the phosphorylated enzyme intermediate. These observations, together with the results obtained for [125I]calmodulin binding to the ATPase, suggest that the stimulation in turnover produced by calmodulin on the ATPase is due to a direct effect on the enzyme. This may provide an independent regulation of the cardiac sarcoplasmic reticulum Ca(2+)-ATPase, in addition to the known regulation mediated by other accessory proteins.
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PMID:Effect of calmodulin on sarcoplasmic reticulum Ca(2+)-ATPase isolated from cardiac muscle. 138 34

Cleavage of caldesmon with chymotrypsin yields a series of fragments which bind both calmodulin and actin and inhibit the binding of myosin subfragments to actin and the subsequent stimulation of ATPase activity. Several of these fragments have been purified by cation exchange chromatography and their amino-terminal sequences determined. The smallest fragment has a molecular mass of about 7.3 kDa and extends from Leu597 to Phe665. This polypeptide inhibits the actin-activated ATPase of myosin S-1; this inhibition is augmented by smooth muscle tropomyosin and relieved by Ca(2+)-calmodulin. The binding of the 7.3-kDa fragment to actin is competitive with the binding of S-1 to actin. Thus, this polypeptide has several of the important features characteristic of intact caldesmon. However, although an intact caldesmon molecule covers between six and nine actin monomers, the 7.3-kDa fragment binds to actin in a 1:1 complex. Comparison of this fragment with others suggests that a small region of caldesmon is responsible for at least part of the interaction with both calmodulin and actin.
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PMID:Localization and characterization of a 7.3-kDa region of caldesmon which reversibly inhibits actomyosin ATPase activity. 138 4

1. Effects of cyclopiazonic acid (CPA), a specific inhibitor of the Ca(2+)-ATPase in sarcoplasmic reticulum (SR) of skeletal and cardiac muscles, on contractile responses induced by Ca(2+)-release from intracellular storage sites were examined in the longitudinal smooth muscle strip of the guinea-pig ileum skinned with beta-escin. 2. Ca(2+)-loading of storage sites (Ca(2+)-uptake) was performed in pCa 6.3 solution. The amount of Ca2+ taken up was monitored by use of the amplitude of contraction following application of 25 mM caffeine or 25 microM inositol 1,4,5-trisphosphate (IP3). 3. Contractile responses to caffeine or IP3 were reduced or abolished when the preceding Ca(2+)-uptake was performed in the presence of 0.1-10 microM CPA. The dose of CPA required to inhibit the contraction induced by caffeine or IP3 by 50% was approximately 0.6 microM. The CPA-sensitive Ca(2+)-uptake completely depended upon the presence of ATP in the solution during Ca(2+)-uptake. 4. When 1 microM CPA was added after Ca(2+)-uptake, the subsequent caffeine- or IP3-induced contraction was not significantly affected by the presence of CPA. 5. Acetylcholine-induced contraction was also almost abolished when the preceding Ca(2+)-uptake was performed in the presence of 10 microM CPA. 6. The relationship between pCa and contraction was not affected by the presence of 10 microM CPA in skinned fibres where Ca2+ storage sites had been destroyed by treatment with A23187. The enhancement of contraction in pCa 6.0 solution by calmodulin was not affected by 10 microM CPA.7. These results suggest that CPA selectively inhibits ATP-dependent Ca2"-uptake into intracellular storage sites in skinned ileal smooth muscle strips. CPA appears to be a potent, reversible, and very specific inhibitor of the Ca2+-pump in the storage sites of smooth muscle, and is an extremely valuable pharmacological tool.
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PMID:Effects of cyclopiazonic acid, a novel Ca(2+)-ATPase inhibitor, on contractile responses in skinned ileal smooth muscle. 138 24

The plasma membrane of the human pathogen Leishmania donovani possesses a high-affinity transmembrane Ca(2+)-ATPase that has its catalytic site oriented toward the cytoplasmic milieu (Ghosh, J., Ray, M., Sarkar, S., and Bhaduri, A. (1990) J. Biol. Chem. 265, 11345-11351). When the enzyme is studied in its more authentic, physiologically relevant, membrane-associated form, it exhibits pronounced sigmoidal kinetics with Ca2+ (K0.5 approximately 700 nM) in a trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid buffering system that effectively complexes all available Mg2+. Addition of exogenous Mg2+ (60 microM) completely abolishes sigmoidicity and establishes strictly hyperbolic kinetics, and the Km for Ca2+ reduces to 100 nM. Mg2+ can be replaced by heterologous calmodulin. The exclusive dependence of the enzyme on only Ca2+ for its activity and its positive allosteric modulation by Mg2+ distinguish this enzyme from other well-characterized plasma membrane Ca(2+)-ATPases. Employing this Ca(2+)-ATPase as the assay system, a soluble endogenous activating protein factor was purified that, by several criteria, corresponds to authentic calmodulin. The parasite calmodulin shifts the kinetics to hyperbolic kinetics, increases the Vmax 2-fold, and most important lowers the Km (approximately 100 nM) to a physiological level. The interaction with endogenous calmodulin thus converts the enzyme from a totally inactive to a fully active state.
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PMID:Allosteric modulation of Leishmania donovani plasma membrane Ca(2+)-ATPase by endogenous calmodulin. 138 52

Myosin I is an actin-based motor responsible for powering a wide variety of motile activities in amebae and slime molds and has been found previously in vertebrates as the lateral bridges within intestinal epithelial cell microvilli. Although neurons exhibit extensive cellular and intracellular motility, including the production of ameboid-like growth cones during development, the proteins responsible for the motor in these processes are unknown. Here, we report the isolation of a partially purified protein fraction from bovine brain that is enriched for a 150-kDa protein; immunochemical and biochemical analyses suggest that this protein possesses a number of functional properties that have been ascribed to myosin I from various sources. These properties include an elevated K(+)-EDTA ATPase, a modest actin-activated Mg(2+)-ATPase, the ability to bind calmodulin, and a ready association with phospholipid vesicles made from phosphatidylserine, but not from phosphatidylcholine. The combination of these properties, together with a molecular mass of 150 kDa (most myosin I molecules found to date have molecular masses in the range 110-130 kDa) yet recognition by an anti-myosin I antibody, suggests the presence of a new member of the myosin I family within mammalian brain.
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PMID:Evidence for a new member of the myosin I family from mammalian brain. 140 85

The inhibitory effect of calmodulin antagonists, synthetic peptide analogs of the pseudosubstrate domain of smooth muscle MLC kinase, and an inhibitor based on the sequence of MLC were examined using bovine aortic actomyosin and isolated chicken gizzard MLC. Much lower concentrations of the peptides were necessary to inhibit actomyosin ATPase activity than to inhibit superprecipitation. In contrast, calmodulin antagonists inhibited both ATPase activity and superprecipitation at similar concentrations. The peptide analogs were competitive with isolated MLC, but not calmodulin, for inhibition of MLC kinase. These results suggest that in addition to the calmodulin dependence of MLC phosphorylation, a second calmodulin-like protein may be important in actin-myosin interactions. The data also suggest that the pseudosubstrate hypothesis may not completely account for regulation of MLC kinase activity.
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PMID:Peptide analogs of the pseudosubstrate domain of smooth muscle myosin light chain kinase inhibit actomyosin ATPase activity at concentrations that do not inhibit superprecipitation. 141 4

In order to identify comparative aspects of the interaction of calmodulin with its target proteins, proton magnetic-resonance studies of complex formation between calmodulin and defined segments of phospholamban and caldesmon have been undertaken. Residues 3-15 in the cytoplasmic region of phospholamban, an integral membrane protein of cardiac sarcoplasmic reticulum believed to regulate the calcium pumping ATPase, are shown to contribute to interaction with calmodulin. Using wheat germ calmodulin specifically modified with a spin-label to provide the spectral means for spatial localisation, these residues of phospholamban were correlated with binding in the vicinity of the probe attached to Cys-27 in the N-terminal domain of calmodulin. This interaction, relevant to the mechanism of calmodulin-dependent phosphorylation of phospholamban that relieves its inhibitory influence on the calcium pump, provides a useful model system for comparative study of the properties of calmodulin-binding domains. We contrast here a calmodulin-binding segment in the C-terminal region of caldesmon localised by 1H-NMR study of the interface(s) between the two proteins. These observations are discussed in the context of other calmodulin-binding sequences.
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PMID:Interaction of calmodulin with phospholamban and caldesmon: comparative studies by 1H-NMR spectroscopy. 142 Mar 31

1. A Mg2+ independent, Ca(2+)-ATPase requiring high concentrations of Ca2+ (5 mM) for the activation, equally distributed in cuticle-muscular-hypodermis, genital organs and gastrointestinal tissues and mainly localized in 10,000 g pellet fraction, was identified in Setaria cervi, a bovine filarial parasite. 2. Filarial enzyme showed Km value of 3.33 mM for ATP as computed from the double reciprocal Lineweaver-Burk plot. 3. The enzyme could be completely solubilized by sonication with about 4-fold increase in specific activity of the enzyme. 4. The enzyme showed about 2-fold activation by the calmodulin fractions isolated from S. cervi and rat brain homogenates. 5. The enzyme was highly sensitive to inhibition with some phenothiazine derivatives. Trifluoperazine was observed to be the most potent inhibitor followed by promethazine and chlorpromazine. 6. Some anthelmintics viz. diethycarbamazine and centperazine were found to be highly potent inhibitors of the enzyme, significant inhibition of filarial Ca(2+)-ATPase was also observed with levamisole and suramine. 7. Studies indicate Ca(2+)-ATPase of S. cervi as a potential chemotherapeutic target.
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PMID:Characterization of Ca(2+)-ATPase of Setaria cervi (Nematoda: Filarioidea): effect of phenothiazines and anthelmintics. 142 25

Caldesmon from chicken gizzard muscle has been examined for its ability to interact with caltropin using affinity chromatography and the fluorescent probe acrylodan. The action of caltropin on the inhibitory effect of caldesmon on actomyosin ATPase was also studied. Like calmodulin, caltropin could release the inhibitory effect of caldesmon in the presence of Ca2+. Complete reversal was obtained when 1 mol of caltropin was added per mol of caldesmon. When caldesmon was applied to caltropin-Sepharose in the presence of Ca2+, most of the caldesmon was bound to the column and could be eluted with EGTA, indicating that there is a direct interaction between caldesmon and caltropin. Acrylodan-labeled caldesmon, when excited at 375 nm, had an emission maximum at 504 nm. Addition of caltropin in the presence of Ca2+ resulted in a nearly 50% increase in fluorescence intensity, and this was accompanied by a blue shift in the emission maximum (i.e., lambda em,max 492 nm), suggesting that the probe now occupies a more nonpolar environment. Titration of caltropin with labeled caldesmon indicated a strong affinity for this protein (Kd was in the order of 8 x 10(-8)-2 x 10(-7) M). However, when caltropin was added to labeled caldesmon in the presence of EGTA, there was no indication of any interaction. Caltropin was at least as potent as calmodulin, if not better, in reversing the inhibitory effect of caldesmon in the presence of calcium, making it a potential Ca2+ factor in regulating caldesmon in smooth muscle.
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PMID:Calcium-dependent regulation of caldesmon by an 11-kDa smooth muscle calcium-binding protein, caltropin. 144 20


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