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PubMed2000

Copper-induced conformational changes in the N-terminal domain of the Wilson disease copper-transporting ATPase.

The Wilson disease copper-transporting ATPase plays a critical role in the intracellular trafficking of copper. Mutations in this protein lead to the accumulation of a toxic level of copper in the liver, kidney, and brain followed by extensive tissue damage and death. The ATPase has a novel amino-terminal domain ( approximately 70 kDa) which contains six repeats of the copper binding motif GMTCXXC. We have expressed and characterized this domain with respect to the copper binding sites and the conformational consequences of copper binding. A detailed analysis of this domain by X-ray absorption spectroscopy (XAS) has revealed that each binding site ligates copper in the +1 oxidation state using two cysteine side chains with distorted linear geometry. Analysis of copper-induced conformational changes in the amino-terminal domain indicates that both secondary and tertiary structure changes take place upon copper binding. These copper-induced conformational changes could play an important role in the function and regulation of the ATPase in vivo. In addition to providing important insights on copper binding to the protein, these results suggest a possible mechanism of copper trafficking by the Wilson disease ATPase.

Adenosine Triphosphatases↗
PubMed2003

Copper chaperones, intracellular copper trafficking proteins. Function, structure, and mechanism of action.

This review summarizes findings on a new family of small cytoplasmic proteins called copper chaperones. The copper chaperones bind and deliver copper ions to intracellular compartments and insert the copper into the active sites of specific partners, copper-dependent enzymes. Three types of copper chaperones have been found in eukaryotes. Their three-dimensional structures have been determined, intracellular target proteins identified, and mechanisms of action have been revealed. The Atx1 copper chaperone binds Cu(I) and interacts directly with the copper-binding domains of a P-type ATPase copper transporter, its physiological partner. The copper chaperone CCS delivers Cu(I) to Cu,Zn-superoxide dismutase 1. Cox17 and Cox11 proteins serve as copper chaperones for cytochrome c oxidase, a copper-dependent enzyme.

Animals↗
PubMed2001

Copper specifically regulates intracellular phosphorylation of the Wilson's disease protein, a human copper-transporting ATPase.

Copper is a trace element essential for normal cell homeostasis. The major physiological role of copper is to serve as a cofactor to a number of key metabolic enzymes. In humans, genetic defects of copper distribution, such as Wilson's disease, lead to severe pathologies, including neurodegeneration, liver lesions, and behavior abnormalities. Here, we demonstrate that, in addition to its role as a cofactor, copper can regulate important post-translational events such as protein phosphorylation. Specifically, in human cells copper modulates phosphorylation of a key copper transporter, the Wilson's disease protein (WNDP). Copper-induced phosphorylation of WNDP is rapid, specific, and reversible and correlates with the intracellular location of this copper transporter. WNDP is found to have at least two phosphorylation sites, a basal phosphorylation site and a site modified in response to increased copper concentration. Comparative analysis of WNDP, the WNDP pineal isoform, and WNDP C-terminal truncation mutants revealed that the basal phosphorylation site is located in the C-terminal Ser(796)-Tyr(1384) region of WNDP. The copper-induced phosphorylation appears to require the presence of the functional N-terminal domain of this protein. The novel physiological role of copper as a modulator of protein phosphorylation could be central to understanding how copper transport is regulated in mammalian cells.

Adenosine Triphosphatases↗
PubMed2004

Mobilization of intracellular copper stores by the ctr2 vacuolar copper transporter.

Copper plays an essential role in processes including signaling to the transcription and protein trafficking machinery, oxidative phosphorylation, iron mobilization, neuropeptide maturation, and normal development. Whereas much is known about intracellular mobilization of ions such as calcium, little information is available on how eukaryotic cells mobilize intracellular copper stores. We describe a mechanism by which the Saccharomyces cerevisiae Ctr2 protein provides bioavailable copper via mobilization of intracellular copper stores. Whereas Ctr2 exhibits structural similarity to the Ctr1 plasma membrane copper importer, microscopic and biochemical fractionation studies localize Ctr2 to the vacuole membrane. We demonstrate that Ctr2 mobilizes vacuolar copper stores in a manner dependent on amino acid residues conserved between the Ctr1 and Ctr2 copper transport family and that ctr2 Delta mutants hyper-accumulate vacuolar copper. Furthermore, a Ctr2 mutant that is mislocalized to the plasma membrane stimulates extracellular copper uptake, supporting a direct role for Ctr2 in copper transport across membranes. These studies identify a novel mechanism for copper mobilization and suggest that organisms cope with copper deprivation via the use of intracellular vesicular stores.

Amino Acid Sequence↗
PubMed1983

Yeast copper-thionein can reconstitute the Japanese-lacquer-tree (Rhus vernicifera) laccase from the Type 2-copper-depleted enzyme via a direct copper(I)-transfer mechanism.

The Type 2-Cu-depleted laccase from the Japanese lacquer tree (Rhus vernicifera) can be reconstituted with CuSO4 aerobically and much more rapidly and efficiently under anaerobic reducing conditions. This is to be related to a more favourable conformation of a laccase in the reduced state, rather than to reduction of the metal ion. In fact, reconstitution with Cu(I)-thionein from baker's yeast (Saccharomyces cerevisiae) only proceeds under anaerobic reducing conditions, via a direct transfer of Cu(I).

Binding Sites↗
PubMed1998

The effect of dietary supplementation with copper sulfate or tribasic copper chloride on broiler performance, relative copper bioavailability, and dietary prooxidant activity.

Three experiments were conducted to study Cu sulfate and tribasic Cu chloride (TBCC) as sources of supplemental Cu for poultry. In Experiment 1, 252 chicks were fed the basal corn-soybean meal diet (26 ppm Cu) supplemented with either 0, 150, 300, or 450 ppm Cu from Cu sulfate or TBCC for 21 d. Chicks fed 450 ppm Cu from sulfate had lower (P < 0.05) feed intake than those consuming other diets. Feeding supplemental Cu increased (P < 0.0001) liver Cu concentration linearly with increasing dietary Cu regardless of Cu source. The slopes of regression of log10 liver Cu on dietary Cu intake did not differ between sources (P > 0.10). Linear regression over nonzero dietary levels of log10 transformed liver Cu concentration (parts per million of DM) on analyzed total Cu intake (micrograms) resulted in a slope ratio estimate of 106+/-19 for bioavailability of Cu from TBCC compared to 100 for that in Cu sulfate. In Experiment 2, a 42-d floor pen study was conducted with 1,260 broiler chicks given the basal corn-soybean meal diet supplemented with 0, 200, 400, or 600 ppm Cu from either feed-grade Cu sulfate or TBCC. Body weight and feed conversion did not differ in birds fed up to 400 ppm Cu from either source. Birds given 600 ppm Cu from either source had lower feed intake, poorer growth, and feed conversion (P < 0.0001). Liver Cu increased (P < 0.0001) linearly with increasing dietary Cu. Based on log10 liver Cu concentration, Cu in TBCC was 112% available compared to 100% for the standard Cu sulfate. In Experiment 3, Cu sources were added to broiler starter diets at concentrations of 25, 100, and 300 ppm Cu and diets were stored at an elevated temperature to examine the effect of particle size on oxidation. Diets were stored at 37 C for up to 20 d and samples were removed at 4-d intervals. At 300 ppm added Cu, oxidation in TBCC diets was lower (P < 0.0001) than oxidation in diets fortified with coarse Cu sulfate, even though TBCC modal diameter for particle size was almost seven times smaller. Oxidation promotion by Cu sulfate was much greater with fine than in coarse sized particles for all three fortification levels.

Animal Feed↗
PubMed1996

Utilization of copper in copper proteinate, copper lysine, and cupric sulfate using the rat as an experimental model.

One hundred twenty male Sprague-Dawley rats, averaging 108.6 g initial body weight, were used in two feeding experiments to evaluate the utilization of Cu in Cu proteinate, Cu lysine, and cupric sulfate. In Exp. 1, 60 rats were randomly assigned to 12 treatments in a 2 x 2 x 3 factorial arrangement of treatments, with Zn supplementation at 0 or 1000 mg/kg diet, Cu supplementation at 5 or 15 mg/kg diet, and Cu form of CuSO4.5H2O, Cu proteinate, or Cu lysine. The purified basal diet contained .81 mg Cu, 20 mg Zn, and 60 mg Fe/kg diet. Experiment 2 was similar to Exp. 1 except Zn was replaced by Fe. In Exp. 1, feed intake of Cu proteinate (15.74 g/d) and Cu lysine (15.74 g/d) treatments was higher (P < .05) than that of CuSO4 (15.33 g/d). Body weight gain and feed intake were increased by high dietary Cu at either requirement or high levels of dietary Zn (P < .05). There were no differences in feed intake or body weight gain among the treatment groups in Exp. 2 (P > .05). The Cu utilization of Cu proteinate and Cu lysine were higher (P < .05) based on the liver Cu content. The rats fed Cu complexes had a higher liver Fe or Zn content (P < .05) than the rats fed CuSO4, suggesting that Cu complexes are absorbed via another mechanism that differs from that of inorganic Cu and does not interfere with Zn and Fe. Spleen Cu content may be a sensitive indicator of Cu status. High dietary Zn decreased Cu utilization, but this effect was overcome by high dietary Cu.

Animals↗
PubMed1998

Tribasic copper chloride and copper sulfate as copper sources for weanling pigs.

We conducted three 28-d experiments involving a total of 915 pigs to assess the relative efficacy of tribasic Cu chloride (Cu2[OH]3Cl) and Cu sulfate pentahydrate (CuSO4.5H20) in diets for weanling pigs. Experiments 1 and 2 were conducted at an experiment station (University of Kentucky), and Exp. 3 was conducted at a commercial feed company's swine research facilities (United Feeds, Inc.). The basal diet was a fortified corn-soybean meal-dried whey diet (1.25% lysine) with no antimicrobials in Exp. 1 or with carbadox (55 mg/kg) in Exp. 2 and 3. In Exp. 1, 135 pigs were weaned at 27 to 31 d and fed the basal diet without or with 100 or 200 ppm Cu from Cu chloride, or 100 or 200 ppm Cu from Cu sulfate from 7.9 to 17.7 kg BW. The 200 ppm level of Cu from Cu sulfate improved ADG (P < .10), and both levels of Cu from Cu chloride tended to improve feed:gain. In Exp. 2, 150 pigs were weaned at 27 to 31 d and fed the basal diet without or with 100, 150, or 200 ppm Cu from Cu chloride, or 200 ppm Cu from Cu sulfate from 8.9 to 20.8 kg BW. Addition of 200 ppm Cu improved ADG (P < .08) and ADFI (P < .01), but not feed:gain. Source of Cu did not affect performance. In Exp. 3, 630 pigs were weaned at 16 to 20 d and fed a common diet for 10 to 12 d until the start of the experimental period. The same experimental diets as used in Exp. 2 were fed from 9.1 to 25.5 kg BW. Both Cu sources improved ADG (P < .01), and sources and levels of Cu did not differ. Liver Cu increased in pigs fed 200 ppm Cu, and Cu sulfate tended to increase liver Cu more than did Cu chloride in one experiment, but not in another experiment. The results indicate that tribasic Cu chloride is as effective as Cu sulfate in improving growth in weanling pigs.

Aging↗
PubMed2004

Copper proteinate in weanling pig diets for enhancing growth performance and reducing fecal copper excretion compared with copper sulfate.

Two 28-d experiments were conducted to evaluate the efficacy of low dietary concentrations of Cu as Cu-proteinate compared with 250 ppm Cu as CuSO4 with growth performance, plasma Cu concentrations, and Cu balance of weanling swine as the criteria. In the production study (Exp. 1), 240 crossbred pigs that averaged 19.8 d of age and 6.31 kg BW initially were group-fed (two or three pigs per pen) the basal diets (Phase 1: d 0 to 14 and Phase 2: d 14 to 28) supplemented with 0 (control), 25, 50, 100, or 200 ppm Cu as Cu-proteinate, or 250 ppm Cu as CuSO4 (as-fed basis). The basal diets contained 16.5 ppm Cu supplied as CuSO4 before supplementation with Cu-proteinate or 250 ppm Cu as CuSO4. There were quadratic responses (P < or = 0.05) in ADFI and ADG for wk 1, Phases 1 and 2, and overall because ADFI was higher for pigs fed 25 or 50 ppm Cu as Cu-proteinate, and ADG increased with increasing Cu-proteinate up to 50 ppm Cu. The Cu-proteinate treatment groups combined had a higher (P < or = 0.05) Phase 2 and overall ADFI and ADG than the CuSO4 group. In the mineral balance study (Exp. 2), 20 crossbred barrows that averaged 35 d of age and 11.2 kg/BW initially were placed in individual metabolism pens with total urine and fecal grab sample collections on d 22 to 26. Treatments were the basal Phase 2 diet supplemented with 0, 50, or 100 ppm Cu as Cu-proteinate, or 250 ppm Cu as CuSO4 (as-fed basis). Treatments did not differ in growth performance criteria. There were linear increases (P < 0.001) in Cu absorption, retention, and excretion (milligrams per day) with increasing Cu-proteinate. Pigs fed 100 ppm Cu as Cu-proteinate absorbed and retained more Cu and excreted less Cu (mg/d, P < or = 0.003) than pigs fed 250 ppm Cu as CuSO4. Plasma Cu concentrations increased linearly (P = 0.06) with increasing Cu-proteinate. In conclusion, weanling pig growth performance was increased by 50 or 100 ppm Cu as Cu-proteinate in our production Exp. 1, but not in our balance Exp. 2, compared with 250 ppm Cu as CuSO4. However, 50 or 100 ppm Cu as Cu-proteinate increased Cu absorption and retention, and decreased Cu excretion 77 and 61%, respectively, compared with 250 ppm Cu as CuSO4.

Animal Feed↗
PubMed2000

Response of diamine oxidase and other plasma copper biomarkers to various dietary copper intakes in the rat and evaluation of copper absorption with a stable isotope.

There is a lack of agreement on index of Cu status and reliable and sensitive biomarkers are still required. The purpose of this present work was to assess in rats the sensitivity of diamine oxidase (DAO) activity, a recently proposed biomarker, to modifications in dietary Cu intake in comparison with other plasma biomarkers of Cu status. We also evaluated the effect of Cu dietary level on Cu and Zn intestinal absorption. Results showed that plasma Cu and plasma caeruloplasmin were significantly decreased at day 8 compared with the control group (7.4 mg Cu/kg diet) while DAO activity was significantly decreased at day 12 of the deficient diet (0.61 mg Cu/kg diet). Cu supplementation (35 mg Cu/kg diet) had no effect on any of the studied biomarkers of Cu status. In Cu-deficient rats plasma Cu and DAO activities were normalized 4 d after return to the control diet while caeruloplasmin was normalized later, at day 11. Apparent absorption values (%) of total Cu or 65Cu isotope were significantly increased in the Cu-deficient rats compared with the other groups and similar in the control and the Cu-supplemented groups. The urinary excretion of total Cu or 65Cu isotope were increased in the Cu-supplemented group compared with the other two groups. Both apparent absorption and urinary excretion of total Zn or 67Zn isotope remained unchanged in the three experimental groups. In conclusion, DAO activity seemed to be less sensitive to Cu deficiency than plasma Cu or caeruloplasmin concentrations. The present study also showed a significant increase in Cu intestinal absorption with dietary Cu restriction but no decrease with Cu supplementation in the rat.

Absorption↗
PubMed2002

Copper allergy from dental copper amalgam?

A 65-year-old female was investigated due to a gradually increasing greenish colour change of her plastic dental splint, which she used to prevent teeth grinding when sleeping. Furthermore, she had noted a greenish/bluish colour change on the back of her black gloves, which she used to wipe her tears away while walking outdoors. The investigation revealed that the patient had a contact allergy to copper, which is very rare. She had, however, had no occupational exposure to copper. The contact allergy may be caused by long-term exposure of the oral mucosa to copper from copper-rich amalgam fillings, which were frequently used in childhood dentistry up to the 1960s in Sweden. The deposition of a copper-containing coating on the dental splint may be caused by a raised copper intake from drinking water, increasing the copper excretion in saliva, in combination with release of copper due to electrochemical corrosion of dental amalgam. The greenish colour change of the surface of the splint is probably caused by deposition of a mixture of copper compounds, e.g. copper carbonates. Analysis by the X-ray diffraction technique indicates that the dominant component is copper oxide (Cu2O and CuO). The corresponding greenish/bluish discoloration observed on the back of the patient's gloves may be caused by increased copper excretion in tears.

Copper↗
PubMed2003

Copper homeostasis and toxicity in the elasmobranch Raja erinacea and the teleost Myoxocephalus octodecemspinosus during exposure to elevated water-borne copper.

Clear nosed skate, Raja erinacea were exposed to 0.10 (control), 0.52 or 1.73 microM copper and sculpin, Myoxocephalus octodecemspinosus were exposed to 0.10 or 1.73 microM copper (as CuSO4) in Salisbury Cove seawater for up to seven days. Skate gill copper concentrations increased 40-50 fold over background in response to copper exposure at both concentrations. In comparison, sculpin gill levels only increased 3-fold. While there was no evidence for internalized copper in the skate arising from the water-borne exposure, sculpin kidneys, but not livers, exhibited elevated copper concentrations after the seven days of exposure. The marked difference in branchial copper accumulation between the skate and the sculpin likely explains why elasmobranchs appear to be more sensitive to metal exposure than most marine teleost fish. Brain tissue from both species and the skate rectal gland contained relatively high background copper concentrations. Copper exposure caused an initial transient reduction in skate plasma total ammonia (Tamm), but eventually led to elevated plasma Tamm. Despite the marked branchial copper accumulation in the skate, there was no reduction in gill Na/K-ATPase activity. Similarly, Na/K-ATPase activity in skate rectal gland and intestine, as well as in sculpin gill and intestine were not affected by copper exposure. Plasma sodium, magnesium and chloride were not affected by copper exposure in either the skate or the sculpin.

Animals↗
PubMed2004

Copper stimulates trafficking of a distinct pool of the Menkes copper ATPase (ATP7A) to the plasma membrane and diverts it into a rapid recycling pool.

MNK (Menkes copper-translocating P-type ATPase, or the Menkes protein; ATP7A) plays a key role in regulating copper homoeostasis in humans. MNK has been shown to have a dual role in the cell: it delivers copper to cuproenzymes in the Golgi compartment and effluxes excess copper from the cell. These roles can be achieved through copper-regulated trafficking of MNK. It has previously been shown to undergo trafficking from the trans -Golgi network to the plasma membrane in response to elevated copper concentrations, and to be endocytosed from the plasma membrane to the trans -Golgi network upon the removal of elevated copper. However, the fundamental question as to whether copper influences trafficking of MNK to or from the plasma membrane remained unanswered. In this study we utilized various methods of cell-surface biotinylation to attempt to resolve this issue. These studies suggest that copper induces trafficking of MNK to the plasma membrane but does not affect its rate of internalization from the plasma membrane. We also found that only a specific pool of MNK can traffic to the plasma membrane in response to elevated copper. Significantly, copper appeared to divert MNK into a fast-recycling pool and prevented it from recycling to the Golgi compartment, thus maintaining a high level of MNK in the proximity of the plasma membrane. These findings shed new light on the cell biology of MNK and the mechanism of copper homoeostasis in general.

Adenosine Triphosphatases↗
PubMed2004

Copper pathways in Plasmodium falciparum infected erythrocytes indicate an efflux role for the copper P-ATPase.

Copper, like iron, is a transition metal that can generate oxygen radicals by the Fenton reaction. The Plasmodium parasite invades an erythrocyte host cell containing 20 microM copper, of which 70% is contained in the Cu/Zn SOD (cuprozinc superoxide dismutase). In the present study, we follow the copper pathways in the Plasmodium-infected erythrocyte. Metal-determination analysis shows that the total copper content of Percoll-purified trophozoite-stage-infected erythrocytes is 66% that of uninfected erythrocytes. This decrease parallels the decrease seen in Cu/Zn SOD levels in parasite-infected erythrocytes. Neocuproine, an intracellular copper chelator, arrests parasites at the ring-to-trophozoite stage transition and also specifically decreases intraparasitic levels of Cu/Zn SOD and catalase. Up to 150 microM BCS (2,9-dimethyl-4,7-diphenyl-1,10-phenanthrolinedisulphonic acid), an extracellular copper chelator, has no effect on parasite growth. We characterized a single copy PfCuP-ATPase (Plasmodium falciparum copper P-ATPase) transporter, which, like the Crypto-sporidium parvum copper P-ATPase, has a single copper-binding domain: 'Met-Xaa-Cys-Xaa-Xaa-Cys'. Recombinant expression of the N-terminal metal-binding domain reveals that the protein specifically binds reduced copper. Transcription of the PfCuP-ATPase gene is the highest at late ring stage/early trophozoite, and is down-regulated in the presence of neocuproine. Immunofluorescence and electron microscopy indicate the transporter to be both in the parasite and on the erythrocyte membrane. Both the decrease in total copper and the location of the PfCuP-ATPase gene indicate a copper-efflux pathway from the infected erythrocyte.

Adenosine Triphosphatases↗
PubMed2002

A copper-responsive transcription factor, CRF1, mediates copper and cadmium resistance in Yarrowia lipolytica.

The dimorphic yeast Yarrowia lipolytica is more resistant to high copper concentrations than Saccharomyces cerevisiae. This differential tolerance to copper ions has been observed in several strains arising from non-related isolates. To investigate the molecular basis of this resistance, we obtained several copper-sensitive mutants. By complementation of one of them, we isolated the YlCRF1 gene encoding for a copper-binding transcription factor of 411 amino acids homologous to ScAce1p, CgAmt1p, and ScMac1p. Naturally occurring copper-sensitive strains lack the CRF1 allele. The YlCRF1 transcript is not induced by the addition of copper to the medium. Gene disruption demonstrated that YlCRF1 is responsible for a 4- to 5-fold increase in Y. lipolytica copper tolerance. We further show that strain Deltacrf1 is more sensitive to cadmium but not to other metals. The role of YlCrf1p as a copper-sensitive transcription factor is supported by the finding that the protein is immunolocalized in the nucleus during growth in copper-supplemented but not in copper-free medium. However, in contrast to the S. cerevisiae strain mutated in the metallothionein transcription activator ACE1, Y. lipolytica strain Deltacrf1 is still able to increase metallothionein (MTP) mRNA levels in response to copper addition. CRF1 deletion does not affect superoxide dismutase (SOD) activity either. Our data suggest the existence of one or more different target genes for Crf1p, other than MTP or SOD1, and support its role as a novel copper-responsive transcription factor involved in metal detoxification.

Alleles↗
PubMed2002

The molecular basis of copper homeostasis copper-related disorders.

Copper is an essential trace element that can be extremely toxic in excess due to the pro-oxidant activity of copper ions. Inherited disorders of copper transport, Menkes disease (copper deficiency), and Wilson disease (copper toxicosis) are caused by mutations of two closely related Cu transporting-ATPases, and demonstrate the essentiality and potential toxicity of copper. Other copper toxicosis conditions in humans and animals have been described, but are not well understood at a molecular level. Copper homeostatic mechanisms are being discovered. One such mechanism is copper-induced trafficking of the Cu-ATPases, which allows cells to provide copper to secreted cupro-proteins but also to efflux excess copper. Oxidative damage induced by copper may be involved in the pathogenesis of neurodegenerative conditions such as Alzheimer's disease, familial amyotrophic lateral sclerosis, and prion diseases.

Alzheimer Disease↗