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)

Immunofluorescence and immunogold labeling, together with sucrose gradient separation and Western blot analysis of microsomal subfractions, were employed in parallel to probe the endoplasmic reticulum in the cell body and dendrites of rat cerebellar Purkinje neurons. Two markers, previously investigated in non-nerve cells, the membrane protein p91 (calnexin) and the lumenal protein BiP, were found to be highly expressed and widely distributed to the various endoplasmic reticulum sections of Purkinje neurons, from the cell body to dendrites and dendritic spines. An antibody (denominated anti-rough-surfaced endoplasmic reticulum), which recognized two membrane proteins, p14 and p40, revealed a similar immunogold labeling pattern. However, centrifugation results consistent with a widespread distribution were obtained for p14 only, while p40 was concentrated in the rough microsome-enriched subfractions. The areas enriched in the inositol 1,4,5-triphosphate receptor and thus presumably specialized in Ca2+ transport (stacks of multiple smooth-surfaced cisternae; the dendritic spine apparatus) also exhibited labeling for BiP and p91, and were positive for the anti-rough-surfaced endoplasmic reticulum antibody (presumably via the p14 antigen). Additional antibodies, that yielded inadequate immunocytochemical signals, were employed only by Western blotting of the microsomal subfractions, while the ryanodine receptor was studied by specific binding. The latter receptor and the Ca2+ ATPase, known in other species to be concentrated in Purkinje neurons, exhibited bimodal distributions with a peak in the light and another in the heavy subfractions. A similar distribution was also observed with another lumenal protein, protein disulfide isomerase. Taken as a whole, the results that we have obtained suggest the existence in the endoplasmic reticulum of Purkinje neurons of two levels of organization; the first identified by widespread, probably general markers (BiP, p91, possibly p14 and others), the second by specialization markers, such as the inositol 1,4,5-triphosphate receptor and, possibly, p40, which appear restricted to areas where specific functions appear to be localized.
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PMID:The endoplasmic reticulum of Purkinje neuron body and dendrites: molecular identity and specializations for Ca2+ transport. 133 57

Folding catalysts of the endoplasmic reticulum (ER), such as protein disulfide isomerase (PDI), accelerate the slow chemical steps, such as disulfide bond formation, that accompany protein folding. Molecular chaperones of the ER, notably the heavy chain-binding protein, BiP (grp78), bind and release unfolded proteins in an ATP-dependent fashion. In vitro, the fate of reduced, denatured lysozyme is dependent on whether the substrate interacts first with BiP or PDI. Depending on the ratio of PDI to substrate and order in which the components of the reaction are mixed, PDI can exhibit a foldase/chaperone activity, which increases the rate and extent of lysozyme refolding, or it can function as an anti-chaperone that promotes the formation of inactive, disulfide-linked lysozyme aggregates (Puig, A., and Gilbert, H.F. (1994) J. Biol. Chem. 269, 7764-7771). Reduced, denatured lysozyme, but not the native protein, interacts with BiP and efficiently stimulates its peptide-dependent ATPase activity. When present at substoichiometric amounts, BiP, like PDI, facilitates the formation of large, inactive lysozyme aggregates that are non-covalently associated with BiP. BiP and PDI compete for a limited number of sites in these insoluble aggregates. If BiP is present at a high molar excess, the chaperone binds unfolded lysozyme and inhibits its aggregation by maintaining it in a soluble, yet inactive, conformation, both in the presence or absence of ATP. Increasing concentrations of BiP decrease the extent, but not the initial rate, of refolding, suggesting that BiP and PDI compete for unfolded lysozyme and that the BiP-lysozyme complex is not a very good substrate for PDI either in the presence or absence of ATP. Depending on the BiP and PDI concentrations, unfolded lysozyme may either be efficiently refolded into the native conformation in a PDI-catalyzed reaction, or it may form both soluble and insoluble BiP-lysozyme complexes. In vitro, PDI- and BiP-facilitated aggregation, as well as the competition of the two proteins for substrate, reproduces many of the features of the quality control system of the ER.
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PMID:Anti-chaperone behavior of BiP during the protein disulfide isomerase-catalyzed refolding of reduced denatured lysozyme. 792 93

We previously reported the ability of protein disulfide isomerase (PDI) to undergo an ATP-dependent autophosphorylation. Our efforts to map the modification site have been hindered by the low abundance and instability of the labeling. Results are presented in this paper on the nature of phospho-PDI, which appears as an intermediate with a half-life of 2.5-8.8 min in an ATPase reaction. ATP binds to PDI with high affinity, Kd 9.66 microM, and the kinetic parameters KmATP and kcat of the ATPase reaction were measured by using a pyruvate kinase-lactate dehydrogenase-coupled assay under various conditions. Strikingly, the ATPase reaction is stimulated in the presence of denatured polypeptides, while the disulfide oxidization activity of PDI is not affected by ATP. However, PDI is known to participate in various unrelated functions in the endoplasmic reticulum, and ATP could be involved in the regulation of one of these. The results are discussed in light of recent findings on ATP-chaperone relationships.
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PMID:ATP binding and hydrolysis by the multifunctional protein disulfide isomerase. 857 38

Analysis of 76 kb of newly sequenced DNA, located between map positions 182 and 258 kb in the 330-kb chlorella virus PBCV-1 genome, revealed 175 open reading frames (ORFs) of 65 codons or longer. One hundred and five of these 175 ORFs were considered major ORFs. Twenty-one of the 105 major ORFs resembled proteins in databases including ribonucleotide reductase small subunit, RNase III, thioredoxin, glutaredoxin, protein disulfide isomerase, deoxynucleoside kinase, frog virus 3 ATPase, Acetobacter cellulose synthase, a bacteriophage encoded endonuclease, and two C-5 cytosine DNA methyltransferases. One of the ORFs was the PBCV-1 major capsid protein. The 105 major ORFs were evenly distributed along the genome. One set of ORFs was separated by 543 nucleotides whereas 75 of the ORFs were separated by fewer than 100 nucleotides. Nineteen of the 175 ORFs resembled other PBCV-1 ORFs, suggesting that they represent either gene duplications or gene families.
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PMID:Analysis of 76 kb of the chlorella virus PBCV-1 330-kb genome: map positions 182 to 258. 880 66

Nongenomic actions of thyroid hormone are by definition independent of nuclear receptors for the hormone and have been described at the plasma membrane, various cell organelles, the cytoskeleton, and in cytoplasm. The actions include alterations in solute transport (Ca2+, Na+, glucose), changes in activities of several kinases, including protein kinase C, cAMP-dependent protein kinase and pyruvate kinase M2 (PKM2), effects on efficiency of specific mRNA translation and mRNA t1/2, modulation of mitochondrial respiration, and regulation of actin polymerization (promotion of formation of F-actin). Iodothyronines also can regulate nongenomically the state of contractile elements in vascular smooth muscle cells (VSMC). The physiologic significance at the cellular level of certain of these actions has been demonstrated, for example, in the cases of myocardiocyte Na+ current, red cell Ca2+ content, and the control by hormone-induced alterations in actin solubility of cell surface activity of iodothyronine 5'-monodeiodinase activity and the intracellular distribution of protein disulfide isomerase activity. The physiologic significance of these actions at the organ or system level is less clear, but extranuclear effects of thyroid hormone on myocardial Na+ channel, sarcoplasmic reticulum Ca(2+)-ATPase activity, and contractile state of VSMC may each contribute to acute effects of thyroid hormone on cardiac output that have recently been described clinically. The molecular mechanisms for nongenomic actions are incompletely understood; relevant binding sites and signal transduction pathways have been described for hormone actions on plasma membrane Ca(2+)-ATPase activity, and PKM2 monomer is known to bind T3 and, as a result, prevent activation of the kinase via tetramer formation. Nongenomic actions of thyroid hormone may have different structure-activity relationships of iodothyronines from those effects that depend upon nuclear receptors; they may have different time courses and may invoke complex signal transduction pathways before the action is detected.
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PMID:Nongenomic actions of thyroid hormone. 893 79

The enzyme activities and the protein levels of Cl(-)-ATPase and Na+/K(+)-ATPase were examined in Alzheimer's disease (AD) brains. Cl(-)-ATPase and Na+/K(+)-ATPase activities in AD brains (n = 13) were significantly lower than those in age-matched control brains (n = 12). In contrast, there was no significant difference in anion-insensitive Mg2(+)-ATPase activity between the two groups. Western blot analysis revealed that the protein levels of Cl(-)-ATPase, Na+/K(+)-ATPase and neuron specific Na+/K(+)-ATPase alpha3 isoform were also significantly reduced in AD brains, while the amount of protein disulfide isomerase, one of the house keeping membrane proteins, was not different between the two groups. The data first demonstrated that Cl(-)-ATPase and Na+/K(+)-ATPase are selectively impaired in AD brains, which may reduce the gradients of Na(+), K(+) and Cl(-) across the cell membranes to cause excitotoxic cellular response and the resulting neuronal death.
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PMID:CI-ATPase and Na+/K(+)-ATPase activities in Alzheimer's disease brains. 1021 77

PMA1 is an essential gene encoding the yeast plasma membrane [H(+)]ATPase. A pma1-D378N mutant has a dominant-negative effect on cell growth because both newly synthesized mutant and wild-type Pma1 molecules are retained and degraded in the endoplasmic reticulum (ER). Like other substrates for ER-associated degradation, Pma1-D378N is stabilized in mutants defective in components of the ubiquitination machinery. A genetic selection was performed for eps (ER-retained pma1 suppressing) mutants in which the growth defect caused by the D378N allele is suppressed. In an eps1 mutant, both mutant and wild-type Pma1 molecules are allowed to travel to the plasma membrane; however, normal retention of resident ER proteins Shr3 and Kar2 is not perturbed. Eps1 is a novel membrane protein belonging to the protein disulfide isomerase (PDI) family, and Eps1 co-localizes with Pma1-D378N in the ER. In the absence of Pma1-D378N, ER export of wild-type Pma1 is not affected by eps1 deletion, but export of the plasma membrane protein Gas1 is delayed. Because Eps1 is required for retention and degradation of Pma1-D378N, we propose a model in which Eps1 acts as a novel membrane-bound chaperone in ER quality control.
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PMID:Eps1, a novel PDI-related protein involved in ER quality control in yeast. 1054 9

Anthraniloyl adenosine-5'-triphosphate (Ant-ATP) and etheno-adenosine-5'-triphosphate (epsilon-ATP) complexed to Mg(2+) ions are substrates of protein disulfide isomerase (PDI). epsilon-ATP, coordinated to Tb(3+) ions, was used as a probe of the ATPase binding site. Sensitized luminescence arising from resonance energy transfer from epsilon-adenine to Tb(3+) is quenched by PDI. The luminescence results are discussed in reference to a model in which the distance of separation between epsilon-adenine (donor) and Tb(3+) (acceptor) is increased upon binding of PDI. The interaction of a small peptide of 14 amino acid residues with the b/b' domain of the protein does not influence the ATPase activity. The phosphorescence, fluorescence and fluorescence anisotropy of bound epsilon-ATP are not perturbed by the binding of the small molecular weight peptide to PDI. It is suggested that the peptide and ATP do not share a common binding site on the b/b' domain.
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PMID:A catalytic site of protein disulfide isomerase probed with adenosine-5'-triphosphate analogs. 1100 47

Cholera toxin is assembled from two subunits in the periplasm of Vibrio cholerae and disassembled in the analogous compartment of target cells, the lumen of the endoplasmic reticulum (ER), before a fragment of it, the A1 chain, is transported into the cytosol. We show that protein disulfide isomerase (PDI) in the ER lumen functions to disassemble and unfold the toxin once its A chain has been cleaved. PDI acts as a redox-driven chaperone; in the reduced state, it binds to the A chain and in the oxidized state it releases it. Our results explain the pathway of cholera toxin, suggest a role for PDI in retrograde protein transport into the cytosol, and indicate that PDI can act as a novel type of chaperone, whose binding and release of substrates is regulated by a redox, rather than an ATPase, cycle.
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PMID:Protein disulfide isomerase acts as a redox-dependent chaperone to unfold cholera toxin. 1129 Mar 30

Covalent binding of acyl glucuronides to proteins is considered an initiating event for the organ toxicity of drugs containing a carboxylic acid group. An acyl glucuronide (AcMPAG) of the immunosuppressant mycophenolic acid was described and shown to form covalent adducts with plasma albumin in vivo. The aim of the present investigation was to identify AcMPAG target proteins in the liver and colon of rats treated with mycophenolate mofetil, which may contribute to a better understanding of the mechanisms responsible for the development of side effects during therapy with this drug. Mycophenolate mofetil was administered per os in to Wistar rats (40 mg/kg/day) over 21 days. Proteins in liver and colon homogenates were separated by two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis. AcMPAG labeled protein spots were detected by Western blotting. After in-gel tryptic digestion of the protein spots from parallel gels (n = 2), peptides were characterized by matrix-assisted laser desorption/ionization-time of flight-mass spectrometry. Data base searching identified AcMPAG target proteins. Tryptic peptides with sufficient signal intensities were subjected to post-source decay analysis. Three proteins in the liver (ATPase/ATP synthase (alpha and beta subunits), protein disulfide isomerase A3 and selenium binding protein) and one protein in the colon (selenium binding protein) were identified as targets for AcMPAG. ATPase/ATP synthase and protein disulfide isomerase are essential proteins involved in the control of the energy and redox state of the cells, whereas the physiological role of selenium binding protein is not fully understood. This study shows for the first time the formation of adducts between tissue proteins and AcMPAG. Whether this chemical modification is associated with compromised protein function and drug toxicity remains to be investigated.
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PMID:Identification of protein targets for mycophenolic acid acyl glucuronide in rat liver and colon tissue. 1535 47


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