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At least 523 records · Page 29Linked to original sources
PubMed2003

Copper-induced trafficking of the cU-ATPases: a key mechanism for copper homeostasis.

The Menkes protein (MNK) and Wilson protein (WND) are transmembrane, CPX-type Cu-ATPases with six metal binding sites (MBSs) in the N-terminal region containing the motif GMXCXXC. In cells cultured in low copper concentration MNK and WND localize to the transGolgi network but in high copper relocalize either to the plasma membrane (MNK) or a vesicular compartment (WND). In this paper we investigate the role of the MBSs in Cu-transport and trafficking. The copper transport activity of MBS mutants of MNK was determined by their ability to complement a strain of Saccharomyces cerevisiae deficient in CCC2 (delta ccc2), the yeast MNK/WND homologue. Mutants (CXXC to SXXS) of MBS1, MBS6, and MBSs1-3 were able to complement delta ccc2 while mutants of MBS4-6, MBS5-6 and all six MBS inactivated the protein. Each of the inactive mutants also failed to display Cu-induced trafficking suggesting a correlation between trafficking and transport activity. A similar correlation was found with mutants of MNK in which various MBSs were deleted, but two constructs with deletion of MBS5-6 were unable to traffic despite retaining 25% of copper transport activity. Chimeras in which the N-terminal MBSs of MNK were replaced with the corresponding MBSs of WND were used to investigate the region of the molecules that is responsible for the difference in Cu-trafficking of MNK and WND. The chimera which included the complete WND N-terminus localized to a vesicular compartment, similar to WND in elevated copper. Deletions of various MBSs of the WND N-terminus in the chimera indicate that a targeting signal in the region of MBS6 directs either WND/MNK or WND to a vesicular compartment of the cell.

Adenosine Triphosphatases↗
PubMed1999

Structure-function analysis of the protein-binding domains of Mac1p, a copper-dependent transcriptional activator of copper uptake in Saccharomyces cerevisiae.

The Mac1 protein in Saccharomyces cerevisiae is essential for the expression of yeast high affinity copper uptake. A positive transcription factor, Mac1p binds via its N-terminal domain to GCTC elements in the promoters of CTR1 and FRE1, encoding a copper permease and metal reductase, respectively. Mac1p-dependent transcriptional activation is negatively regulated by copper. We have mapped the domains in Mac1p responsible for its nuclear localization and for the protein-protein interactions that underlie its transcriptional activity. Immunofluorescence studies indicate that Mac1p contains two nuclear localization signals, one each in the N- and C-terminal halves of the protein. Yeast one-hybrid analysis demonstrates that the copper-dependent transcriptional activity in Mac1p resides primarily in a cysteine-rich element encompassing residues 264-279. Two-hybrid analysis indicates that a copper-independent Mac1p-Mac1p interaction linked to DNA binding is due primarily to a predicted helix in the C-terminal region of the protein encompassing residues 388-406. Point mutations within this putative helix abrogate the Mac1-Mac1 interaction in vivo and formation of a ternary (Mac1p)(2).DNA complex in vitro. When produced in normal abundance, Mac1pI396D and Mac1pF400D helix mutants do not support transcriptional activation in vivo consistent with an essential Mac1p dimerization in transcriptional activation. Lastly, the one- and two-hybrid data indicate that an intramolecular interaction between the DNA-binding and transactivation domains negatively modulates Mac1p activity.

Binding Sites↗
PubMed1978

Elevations in serum copper, erythrocytic copper, and ceruloplasmin concentrations in smokers.

Previous investigators have reported significant elevations of serum copper and ceruloplasmin levels in lymphoma patients and subjects using estrogen, but have not taken into account the smoking habits of these populations. In order to determine whether smoking had any effect on these variables, the authors examined five groups for serum and erythrocytic copper and ceruloplasmin levels: 40 healthy subjects, 14 users of oral contraceptives, 25 smokers, 14 nonsmoking pretreatment lymphoma patients, and eight treated lymphoma patients. Significant elevations of serum copper and ceruloplasmin in pretreatment lymphoma patients, treated patients, and estrogen users were found, confirming previous reports. In addition, all groups had elevations of erythrocytic copper compared with the healthy subjects. Also, significant elevations of serum copper (P less than .0053) and ceruloplasmin (P less than .0001) were found in smoking relative to nonsmoking subjects. No correlation between duration of smoking and these elevations was found.

Adolescent↗
PubMed2006

Copper resistance in Enterococcus faecium, mediated by the tcrB gene, is selected by supplementation of pig feed with copper sulfate.

The tcr gene cluster mediates in vitro copper resistance in Enterococcus faecium. Here we describe the selection of tcr-mediated copper resistance in E. faecium in an animal feeding experiment with young pigs fed 175 mg copper/kg feed (ppm), which is the concentration commonly used for piglets in European pig production. tcr-mediated copper resistance was not selected for in a control group fed low levels of copper (6 ppm). We also show coselection of macrolide- and glycopeptide-resistant E. faecium in the animal group fed the high level of copper. Finally, we identify the tcr genes in the enterococcal species E. mundtii, E. casseliflavus, and E. gallinarum for the first time.

Animal Feed↗
PubMed1979

The state of the device and copper levels in the products of conception in women becoming pregnant with a copper-bearing IUD in situ.

Of the 8 pregnancies studied, 2 were of small gestational sacs with blighted ova and were associated with devices in which the copper wire had very high detectable X-ray emissions for copper (greater than 90%). In 2 other pregnancies intrauterine deaths had occurred by the time of termination at 13 and 17 weeks and copper levels in the products of conception were variable. There was no abnormality of the fetus in the term pregnancy but it seems possible that copper can affect the early growth and development of the embryo. On only 1 of the 8 devices was any great amount of calcium deposited and it is therefore considered unlikely that calcium deposition increases the risk of pregnancy by preventing the release of copper.

Adult↗
PubMed1989

Metallothionein and copper in liver disease with copper retention--a histopathological study.

We have examined the relationship between (a) histochemically demonstrable copper using rubeanic acid, (b) copper-associated protein (CAP) using orcein, and (c) immunoreactive metallothionein (MT) using DNP hapten sandwich staining and have correlated these with histological lesions in 95 liver biopsies from patients with conditions associated with hepatic copper retention, 4 fetal livers, and 25 histologically normal adult controls. No copper or CAP was present in normal adult liver but periportal CAP was present in fetal liver. MT was present in hepatocytes of normal livers with a predominantly perivenular (centrilobular) cytoplasmic distribution varying in staining intensity; all fetal hepatocytes stained strongly for MT. Fifty-two of 95 (55 per cent) abnormal livers contained CAP and 42 (44 per cent) contained both CAP and copper. In CAP-positive livers, the commonest histological lesions were piecemeal necrosis and cholestasis. CAP was present in (a) 15/15 cases of primary biliary cirrhosis including early cases with minimal pathology; and (b) 5/5 cases of Wilson's disease, 6/6 cases of biliary atresia, and 3/9 cases of sclerosing cholangitis. In other conditions, it was present in 25-50 per cent of cases. MT distribution was abnormal in most CAP-positive livers. Necrotic hepatocytes were intensely MT-positive and in Wilson's disease had a characteristic appearance.

Copper↗
PubMed1990

Age-related changes in metallothionein, copper, copper-associated protein, and lipofuscin in human liver: a histochemical and immunohistochemical study.

The relationship between immunohistochemically demonstrable hepatic metallothionein (MT) and age was studied in histologically normal livers from 12 fetuses (13-28 weeks' gestation) and 19 children (birth-4 years). In addition, the relationships between copper (rubeanic acid-positive), copper-associated protein (orcein-positive), lipofuscin (periodic acid Schiff after diastase digestion and Schmorls-positive), and MT (immunostaining) were studied. The fetal livers showed periportal and patchy mid-zone copper-associated protein and lipofuscin granules, together with strong diffuse cytoplasmic and nuclear MT immunostaining. On the other hand, the livers of the children over 6 months of age showed no copper-associated protein or lipofuscin granules, and minimal or no cytoplasmic MT immunostaining (one case showed nuclear MT immunostaining). The DPAS and Schmorls-positive lipofuscin granules appeared to be identical to the orcein-positive copper-associated protein granules which were consistently negative on MT immunostaining. The demonstration of cytoplasmic granular orcein positivity or diffuse non-granular MT immunostaining in liver above the age of 6 months would appear to be of pathological significance.

Aging↗
PubMed1995

Escherichia coli K-12 copper-containing monoamine oxidase: investigation of the copper binding ligands by site-directed mutagenesis, elemental analysis and topa quinone formation.

Copper-containing monoamine oxidase (EC 1.4.3.6) from Escherichia coli is a periplasmic enzyme containing topa quinone in addition to divalent copper as a cofactor. The amino acid sequence of E. coli monoamine oxidase was compared to several cloned amine oxidase genes and five well-conserved histidine residues were found. Site-directed mutagenesis studies were performed to determine which histidine residue serves as the binding ligand to the copper. Enzyme activity, absorption spectrum, and atomic absorption spectrophotometry of the mutant enzymes indicated that histidines 470, 554, and 556 are the copper binding ligands. The absorption spectra of phenylhydrazine derivatives suggested that copper is necessary for topa quinone formation.

Amino Acid Sequence↗
PubMed2001

CueO is a multi-copper oxidase that confers copper tolerance in Escherichia coli.

The putative multi-copper oxidase CueO had previously been implicated in intrinsic copper resistance in Escherichia coli. In this report we showed that the presence of CueO in the periplasm protected alkaline phosphatase from copper-induced damage. CueO contained four copper atoms per molecule and displayed spectroscopic properties typical of blue copper oxidases. CueO catalyzed the oxidation of p-phenylenediamine (pPD), 2,6-dimethoxyphenol (DMP) and exhibited ferroxidase activity in vitro.

Alkaline Phosphatase↗
PubMed1987

Copper and selenium deficiency in cattle: an evaluation of methods of oral therapy and an observation of a copper-selenium interaction.

The efficacies of oxidised copper particles, selenium bullets and soluble glass bullets in raising the copper and/or selenium reserves of young cattle marginally deficient in both trace elements were examined. Selenium bullets were associated with a reduced copper uptake when selenium bullets and oxidised copper particles were given together. Responses in liveweight gains to trace-element supplementation and relationships between copper or selenium in blood components and liver are presented.

Administration, Oral↗
PubMed1979

Effects of copper on the sabellid polychaete, Eudistylia vancouveri: I. Concentration limits for copper accumulation.

Three experiments with a sabellid polychaete (Eudistylia vancouveri) show the threshold concentration for increasing copper accumulation with time to lie between 3 and 6 micrograms/L total copper in seawater during winter conditions. The branchial crown, probably the major absorptive site, concentrated more copper than the body. Accumulation was influenced by size but not by sex. Our studies indicate that the body burden of copper will increase above natural levels in areas of industrial discharge where copper levels are above the threshold limit for accumulation.

Animals↗
PubMed1983

Determination of formation constants of copper(II) complexes of Adler medium components with a solid-state copper(II) ion-selective electrode.

A general method for the determination of overall conditional formation constants of copper(II) complexes of mycoplasma growth medium (Adler) constituents together with the protonation constants of the complexing ligands was developed. In Adler medium a total of 0.204 +/- 0.004 molar copper binding sites proved to be present with log beta 2 = 8.14 +/- 0.05 (mu = 0.11) and log Ka = 6.14 +/- 0.004. Conditional overall formation constants were calculated at various pH values. Free copper(II) ion concentrations were calculated as a function of the total added amount of copper(II) and pH. The consequences of these findings for the determination of the growth inhibition of mycoplasmas by copper complexes of 2,2'-bipyridyl analogues are stressed.

Chemical Phenomena↗
PubMed2001

Independent evolution of heavy metal-associated domains in copper chaperones and copper-transporting atpases.

Copper chaperones are small cytoplasmic proteins that bind intracellular copper (Cu) and deliver it to Cu-dependent enzymes such as cytochrome oxidase, superoxide dismutase, and amine oxidase. Copper chaperones are similar in sequence and structure to the Cu-binding heavy metal-associated (HMA) domains of Cu-transporting ATPases (Cu-ATPases), and the genes for copper chaperones and Cu-ATPases are often located in the same operon. Phylogenetic analysis shows that Cu chaperones and HMA domains of Cu-ATPases represent ancient and distinct lineages that have evolved largely independently since their initial separation. Copper chaperone-Cu-ATPase operons appear to have evolved independently in different prokaryotic lineages, probably due to a strong selective pressure for coexpression of these genes.

Adenosine Triphosphatases↗
PubMed1989

Behavior of [185W]thiotungstates injected into sheep and the influence of copper: their fate and the effect of the compounds upon plasma copper.

[185W]trithio- and tetrathiotungstates (0.5 mg W) were injected intravenously into sheep. The compounds circulated in plasma bound reversibly to plasma proteins, particularly to albumin. After the first few minutes, levels declined exponentially with a T 1/2 of 12-14 hr. The initial movement of [185W]trithiotungstate from the plasma compartment was delayed transiently by the immediate injection of copper (2-6 mg); the longer-term metabolism was unaffected. The final fate of the compounds appeared to be hydrolysis and excretion in urine as [185W]tungstate. 185W from [185W]trithiotungstate appeared more rapidly than from [185W]tetrathiotungstate, but in both the rate was unaffected by copper injections. Since the appearance in urine did not correspond to the disappearance from plasma, it was suggested that the hydrolysis occurred in extravascular tissues and that the liver might be the site. A control experiment showed that [185W]tungstate in plasma was very rapidly cleared (and appeared in urine). At higher W levels (25-50 mg W per sheep per day), systematic copper metabolism was perturbed since plasma copper levels rose. The experiments demonstrated that in sheep the behavior and the effects of thiotungstates and thiomolybdates are sufficiently similar for 185W to be used as a more convenient alternative to 99Mo for longer-term studies on the interaction of the compounds with copper metabolism in animals.

Animals↗
PubMedDate not supplied

Does CSF copper level in Wilson disease reflect copper accumulation in the brain?

The levels of copper and ceruloplasmin in the cerebrospinal fluid (CSF) of patients with Wilson disease were investigated. Ceruloplasmin concentrations in the CSF of all patients were almost the same but were lower than those of the controls. CSF copper concentrations in patients without neurologic signs were within the normal range, 22 +/- 6 ng/ml. In contrast, CSF copper concentrations in patients with neurologic signs (69-98 ng/ml) were significantly higher than the normal levels before and at the beginning of the treatment with D-penicillamine; it gradually decreased in response to treatment. These results suggest that the appearance of neurologic manifestations in Wilson disease is not related to the CSF ceruloplasmin concentration. The CSF copper concentration in this disease appears to reflect copper accumulation in the brain and may be useful as a marker for monitoring therapy.

Adolescent↗
PubMed2006

Hepatocyte nuclear structure and subcellular distribution of copper in zebrafish Brachydanio rerio and roach Rutilus rutilus (Teleostei, Cyprinidae) exposed to copper sulphate.

Copper is a trace element essential to life, but also a heavy metal with toxic effect clearly demonstrated. Cu induced perturbations in fish liver are well documented but the variability of the reported results is large. In this study two cyprinids, zebrafish and roach, were exposed to copper. Reported histocytological changes are either adaptative or degenerative depending on fish species, concentration of metal, and duration of exposure. Hepatic subcellular distribution of copper was determined by X-ray microanalysis in control and Cu-exposed roach and zebrafish. Sublethal copper sulphate contamination induced the development of a particular nucleolar alteration forming a network or honeycomb like structure in liver. This perturbation is observable in almost all the hepatocytes of zebrafish and roach exposed to copper for a minimum of 4 days of exposure. It seemed to concern more precisely the pars fibrosa. X-ray microanalysis showed that the appearance of network nucleolus was in relation to a Cu accumulation. Cu deposit was well located in the network as pars granulosa and nucloplasm showed very lower metal concentrations. The origin and consequence of network structure in nucleolus was discussed.

Animals↗
PubMed2006

1,1'-Xylyl bis-1,4,8,11-tetraaza cyclotetradecane: a new potential copper chelator agent for neuroprotection in Alzheimer's disease. Its comparative effects with clioquinol on rat brain copper distribution.

Dysfunction of copper metabolism leading to its excess or deficiency results in severe ailments. Recently, neurodegenerative disorders such as Alzheimer's disease have been associated with copper metabolism. Compounds having the ability to reduce copper levels in brain or to affect its distribution could have neuroprotective effects, mainly through a downregulation of the transcription of amyloid peptide precursor (APP). We report here the biological effect of compound 1,1'-xylyl bis-1,4,8,11-tetraaza cyclotetradecane, which specifically affects copper concentration in the brain cortex region. Its copper homeostatic activity is compared with that of clioquinol, a well-known drug, which has been recently reported as an active A beta-peptide clearance drug in vivo for Alzheimer's patients.

Alzheimer Disease↗
PubMed2006

Seasonal and spatial patterns of metals at a restored copper mine site. I. Stream copper and zinc.

Seasonal and spatial variations in metal concentrations and pH were found in a stream at a restored copper mine site located near a massive sulfide deposit in the Foothill copper-zinc belt of the Sierra Nevada, California. At the mouth of the stream, copper concentrations increased and pH decreased with increased streamflow after the onset of winter rain and, unexpectedly, reached extreme values 1 or 2 months after peaks in the seasonal hydrographs. In contrast, aqueous zinc and sulfate concentrations were highest during low-flow periods. Spatial variation was assessed in 400 m of reach encompassing an acidic, metal-laden seep. At this seep, pH remained low (2-3) throughout the year, and copper concentrations were highest. In contrast, the zinc concentrations increased with downstream distance. These spatial patterns were caused by immobilization of copper by hydrous ferric oxides in benthic sediments, coupled with increasing downstream supply of zinc from groundwater seepage.

California↗