SEARCH · PubMed Health

Results for “Copper-Transporting ATPases”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

589 records · Page 33Linked to original sources

PubMed1999

RESPONSIVE-TO-ANTAGONIST1, a Menkes/Wilson disease-related copper transporter, is required for ethylene signaling in Arabidopsis.

Ethylene is an important regulator of plant growth. We identified an Arabidopsis mutant, responsive-to-antagonist1 (ran1), that shows ethylene phenotypes in response to treatment with trans-cyclooctene, a potent receptor antagonist. Genetic epistasis studies revealed an early requirement for RAN1 in the ethylene pathway. RAN1 was cloned and found to encode a protein with similarity to copper-transporting P-type ATPases, including the human Menkes/Wilson proteins and yeast Ccc2p. Expression of RAN1 complemented the defects of a ccc2delta mutant, demonstrating its function as a copper transporter. Transgenic CaMV 35S::RAN1 plants showed constitutive expression of ethylene responses, due to cosuppression of RAN1. These results provide an in planta demonstration that ethylene signaling requires copper and reveal that RAN1 acts by delivering copper to create functional hormone receptors.

Alkenes↗

PubMed2000

The high copper tolerance of Candida albicans is mediated by a P-type ATPase.

The pathogenic yeast Candida albicans has higher resistance than the baker's yeast Saccharomyces cerevisiae to elevated concentrations of copper. To understand the basis of this differential resistance, we performed a functional screen for C. albicans genes involved in copper detoxification. Here, we report the isolation of two such genes: a metallothionein, CaCUP1, and a copper-transporting P-type ATPase, CaCRP1. Both genes are induced by extracellular copper. Gene disruptions indicated that the copper extrusion pump is responsible for the unusual resistance of C. albicans to copper, whereas the metallothionein is responsible for the residual copper resistance of the Cacrp1Delta mutant. We show further that under acidic and anaerobic conditions, such as prevail in the natural niche of C. albicans, the digestive tract of animals, CaCRP1 function becomes essential for survival in the presence of even very low copper concentrations. These observations suggest that copper in the gastrointestinal tract may present a toxic challenge to which enteric organisms had to adapt.

Adenosine Triphosphatases↗

PubMed1999

The role of GMXCXXC metal binding sites in the copper-induced redistribution of the Menkes protein.

The Menkes protein (MNK or ATP7A) is a transmembrane, copper-transporting CPX-type ATPase, a subgroup of the extensive family of P-type ATPases. A striking feature of the protein is the presence of six metal binding sites (MBSs) in the N-terminal region with the highly conserved consensus sequence GMXCXXC. MNK is normally located in the trans-Golgi network (TGN) but has been shown to relocalize to the plasma membrane when cells are cultured in media containing high concentrations of copper. The experiments described in this report test the hypothesis that the six MBSs are required for this copper-induced trafficking of MNK. Site-directed mutagenesis was used to convert both cysteine residues in the conserved MBS motifs to serines. Mutation of MBS 1, MBS 6, and MBSs 1-3 resulted in a molecule that appeared to relocalize normally with copper, but when MBSs 4-6 or MBSs 1-6 were mutated, MNK remained in the TGN, even when cells were exposed to 300 microM copper. Furthermore, the ability of the MNK variants to relocalize corresponded well with their ability to confer copper resistance. To further define the critical motifs, MBS 5 and MBS 6 were mutated, and these changes abolished the response to copper. The region from amino acid 8 to amino acid 485 was deleted, resulting in mutant MNK that lacked 478 amino acids from the N-terminal region, including the first four MBSs. This truncated molecule responded normally to copper. Moreover, when either one of the remaining MBS 5 and MBS 6 was mutated to GMXSXXS, the resulting proteins were localized to the TGN in low copper and relocalized in response to elevated copper. These experiments demonstrated that the deleted N-terminal region from amino acid 8 to amino acid 485 was not essential for copper-induced trafficking and that one MBS close to the membrane channel of MNK was necessary and sufficient for the copper-induced redistribution.

Adenosine Triphosphatases↗

PubMed2005

Molecular insight into extreme copper resistance in the extremophilic archaeon 'Ferroplasma acidarmanus' Fer1.

'Ferroplasma acidarmanus' strain Fer1 is an extremely acidophilic archaeon involved in the genesis of acid mine drainage, and was isolated from copper-contaminated mine solutions at Iron Mountain, CA, USA. Here, the initial proteomic and molecular investigation of Cu(2+) resistance in this archaeon is presented. Analysis of Cu(2+) toxicity via batch growth experiments and inhibition of oxygen uptake in the presence of ferrous iron demonstrated that Fer1 can grow and respire in the presence of 20 g Cu(2+) l(-1). The Fer1 copper resistance (cop) loci [originally detected by Ettema, T. J. G., Huynen, M. A., de Vos, W. M. & van der Oost, J. Trends Biochem Sci 28, 170-173 (2003)] include genes encoding a putative transcriptional regulator (copY), a putative metal-binding chaperone (copZ) and a putative copper-transporting P-type ATPase (copB). Transcription analyses demonstrated that copZ and copB are co-transcribed, and transcript levels were increased significantly in response to exposure to high levels of Cu(2+), suggesting that the transport system is operating for copper efflux. Proteomic analysis of Fer1 cells exposed to Cu(2+) revealed the induction of stress proteins associated with protein folding and DNA repair (including RadA, thermosome and DnaK homologues), suggesting that 'Ferroplasma acidarmanus' Fer1 uses multiple mechanisms for resistance to high levels of copper.

Copper↗

PubMed2005

Two P-type ATPases are required for copper delivery in Arabidopsis thaliana chloroplasts.

Copper delivery to the thylakoid lumen protein plastocyanin and the stromal enzyme Cu/Zn superoxide dismutase in chloroplasts is required for photosynthesis and oxidative stress protection. The copper delivery system in chloroplasts was characterized by analyzing the function of copper transporter genes in Arabidopsis thaliana. Two mutant alleles were identified of a previously uncharacterized gene, PAA2 (for P-type ATPase of Arabidopsis), which is required for efficient photosynthetic electron transport. PAA2 encodes a copper-transporting P-type ATPase with sequence similarity to PAA1, which functions in copper transport in chloroplasts. Both proteins localized to the chloroplast, as indicated by fusions to green fluorescent protein. The PAA1 fusions were found in the chloroplast periphery, whereas PAA2 fusions were localized in thylakoid membranes. The phenotypes of paa1 and paa2 mutants indicated that the two transporters have distinct functions: whereas both transporters are required for copper delivery to plastocyanin, copper delivery to the stroma is inhibited only in paa1 but not in paa2. The effects of paa1 and paa2 on superoxide dismutase isoform expression levels suggest that stromal copper levels regulate expression of the nuclear genes IRON SUPEROXIDE DISMUTASE1 and COPPER/ZINC SUPEROXIDE DISMUTASE2. A paa1 paa2 double mutant was seedling-lethal, underscoring the importance of copper to photosynthesis. We propose that PAA1 and PAA2 function sequentially in copper transport over the envelope and thylakoid membrane, respectively.

Amino Acid Sequence↗

PubMed2004

Role of a Streptococcus gordonii copper-transport operon, copYAZ, in biofilm detachment.

Streptococcus gordonii is a pioneer oral bacterium that is associated with the initiation of dental plaque development. Located downstream of the S. gordonii adc operon, which is involved in competence and biofilm formation, were three open reading frames, designated copY, copA and copZ. These open reading frames were homologous to the copYAZ genes in Streptococcus mutans that are involved in copper homeostasis and biofilm detachment. This study examined whether copYAZ genes play any role in the biofilm formation and detachment of S. gordonii. The copY gene encodes a 143-amino acid protein homologous to the negative transcriptional regulator of a copper-transport operon, copA encodes a 748-amino acid copper-transporting P-type ATPase, and copZ encodes a 69-amino acid putative metallochaperone protein in S. mutans. Each open reading frame in the copYAZ operon in S. gordonii was inactivated by insertional mutation and the growth, biofilm formation and detachment of each mutant were examined. S. gordonii copY::specR, copA::specR, and copZ::specR mutants were able to form biofilms on both polystyrene and glass surfaces. However, inactivation of copZ and to a lesser extent copY resulted in phenotypes that were defective in biofilm detachment, which is consistent with previous observations in S. mutans and suggests that the trace element copper might influence biofilm detachment of bacterial biofilms.

Bacterial Adhesion↗

PubMed2006

Copper in medicine: homeostasis, chelation therapy and antitumor drug design.

As one of the most important essential transition metals, copper is involved in a variety of biological processes such as embryo development, connective tissue formation, temperature control and nerve cell function. It is also related to severe diseases such as Wilson's and Menkes diseases and some neurological disorders. Novel components of copper homeostasis include copper-transporting P-type ATPases, Menkes and Wilson proteins, and copper chaperones in humans have been identified and characterized at the molecular level. These findings have paved the way towards better understanding of the role of copper deficiency or copper toxicity in physiological and pathological conditions. Therefore, organic compounds that can interfere with copper homeostasis may find therapeutic application in copper-dependent diseases. The antitumor activity of copper complexes was reported several decades ago, and many new complexes have demonstrated great antitumor potential. Copper complexes may have relatively lower side effects than platinum-based drugs, and are suggested to be able to overcome inherited or acquired resistance of cisplatin. In this overview, the most recent advances in copper homeostasis, copper-related chelation therapy and design of copper-based antitumor complexes will be summarized.

Antineoplastic Agents↗

PubMed2000

Foreword: from classic bile physiology to cloned transporters.

Uptake of drugs and metabolites from the circulation into the liver is facilitated by transporter proteins in the basolateral membrane of the hepatocyte. Among these proteins are the sodium taurocholate cotransporting protein, various multispecific transporters for organic anions and cations, transporters for glucose, amino acids, and prostaglandins. The canalicular membrane contains a number of ATP-dependent transporters belonging to the families of P-glycoproteins and multidrug resistance-associated proteins. Transport across the canalicular membrane represents the rate-determining step in the secretion of compounds from blood to bile. Mutations of genes encoding these canalicular transporters are associated with liver diseases such as progressive familial intrahepatic cholestasis and Dubin-Johnson syndrome. Wilson's disease appears to be due to a defect of a copper-transporting P-type ATPase. Also, bile ductuli contribute to bile formation. Mutations in the CFTR gene, encoding a chloride channel in bile duct epithelial cells, leads to the hepatic component of cystic fibrosis.

Bile↗

PubMed2003

[Wilson's disease].

Wilson's disease is an autosomal recessive disorder of copper metabolism. The Wilson disease protein is a copper-transporting P-type ATPase, ATP7B, the malfunction of which results in the toxic accumulation of copper in the liver and brain, causing the hepatic and/or neurological symptoms accompanying this disease. Patients present, generally between the ages of 10 and 40 years, with liver disease, neurological disease of a movement disorder type, or behavioral abnormalities, and often with a combination of these. Because Wilson's disease is effectively treated, it is extremely important for physicians to learn to recognize and diagnose the disease. The laboratory diagnosis of Wilson's disease is confirmed by decreased serum ceruloplasmin, increased urinary copper content, and elevated hepatic copper concentration. Molecular genetic analysis is complex as more than 200 unique mutations have been identified and most individuals are compound heterozygotes. The treatment of Wilson's disease must be life long. Copper chelation with penicillamine is an effective therapy in most patients. Another chelating agent which has been used successfully as the initial therapy is trientine. The search for new anticopper drugs for Wilson's disease is culminating in two excellent new drugs: zinc for maintenance therapy and ammonium tetrathiomolybdate (which is to date still an experimental drug) for initial therapy. Liver transplantation is indicated for the fulminant form and in those patients with severe disease not responding to optimal medical management. This paper reviews the pathogenesis, pathology, clinical presentation and diagnosis of the Wilson's disease as well as the most recent views on the molecular genetics and the treatment of this disease.

Hepatolenticular Degeneration↗

PubMed1995

Wilson's disease: a new gene and an animal model for an old disease.

Wilson's disease is an autosomal recessive, inherited disorder of copper metabolism. In normal individuals, copper homeostasis is controlled by the balance between intestinal absorption of dietary copper and hepatic excretion of excess copper in bile. In Wilson's disease, hepatic copper is neither excreted in bile nor incorporated into ceruloplasmin and copper accumulates to toxic levels. The Wilson's disease gene (WND) encodes a putative copper-transporting protein that is expressed almost exclusively in the liver. The predicted structure of the protein product is that of a P-type ATPase with striking homology to bacterial copper transporters and the gene product of another inherited disorder of copper metabolism, Menkes' disease. A rat model of Wilson's disease has recently been identified. The Long-Evans Cinnamon (LEC) rat manifests elevated hepatic copper, defective incorporation of copper into ceruloplasmin, and reduced biliary excretion of copper. The rat homologue of the WND is abnormal in LEC rats. Clinical manifestations of Wilson's disease arise directly from copper-induced damage to hepatocytes (hepatic presentation) or indirectly after the release of copper from the liver with subsequent damage to the brain (neuropsychiatric presentation) and other organs. Genetic heterogeneity (different mutations in a single gene) may account for some of the variability in Wilsonian presentations. The diagnosis of Wilson's disease depends on the demonstration of disordered copper metabolism, manifested as elevated urinary and hepatic copper and low ceruloplasmin levels. However, none of the abnormal findings in Wilson's disease is pathognomonic. Genetic diagnosis, in the absence of family studies, is likely to be difficult since many different mutations result in the disease. Management of Wilson's disease involves decreasing excess levels of copper accumulated in the liver, brain, and other organs. Copper chelation therapy, to increase urinary excretion of copper, is the mainstay of treatment. In addition, oral zinc therapy may be useful at decreasing absorption of dietary copper and rendering tissue copper nontoxic, by increasing the formation of complexes with copper-binding proteins. Liver transplantation can be necessary for individuals with acute hepatic failure or complications of cirrhosis. Gene therapy may evolve in the future; however, medical management is effective in most patients.

Amino Acid Sequence↗

PubMed2001

Characterization of a copper-transport operon, copYAZ, from Streptococcus mutans.

A copper-transport (copYAZ) operon was cloned from the oral bacterium Streptococcus mutans JH1005. DNA sequencing showed that the operon contained three genes (copY, copA and copZ), which were flanked by a single promoter and a factor-independent terminator. copY encoded a small protein of 147 aa with a heavy-metal-binding motif (CXCX(4)CXC) at the C-terminus. CopY shared extensive homology with other bacterial negative transcriptional regulators. copA encoded a 742 aa protein that shared extensive homology with P-type ATPases. copZ encoded a 67 aa protein that also contained a heavy-metal-binding motif (CXXC) at the N-terminus. Northern blotting showed that a 3.2 kb transcript was produced by Cu2+-induced Strep. mutans cells, suggesting that the genes were synthesized as a polycistronic message. The transcriptional start site of the cop operon was mapped and shown to lie within the inverted repeats of the promoter-operator region. Strep. mutans wild-type cells were resistant to 800 microM Cu2+, whereas cells of a cop knock-out mutant were killed by 200 microM Cu2+. Complementation of the cop knock-out mutant with the cop operon restored Cu2+ resistance to wild-type level. The wild-type and the mutant did not show any differences in susceptibility to other heavy metals, suggesting that the operon was specific for copper. By using a chloramphenicol acetyltransferase reporter gene fusion, the cop operon was shown to be negatively regulated by CopY and could be derepressed by Cu2+.

Amino Acid Sequence↗

PubMed1997

The Listeria monocytogenes gene ctpA encodes a putative P-type ATPase involved in copper transport.

A Tn917 transposon derivative was used to construct a lacZ transcriptional fusion mutant in Listeria monocytogenes DRDC8 that displayed increased beta-galactosidase activity in response to cation stress. A 4.3 kb fragment of L. monocytogenes chromosomal DNA flanking the lacZ fusion was cloned and sequenced. A 1962 bp open reading frame was identified, and designated ctpA. Analysis of the deduced 653 amino acid sequence revealed significant similarity to the family of ATP-dependent enzymes involved in copper transport in prokaryotes and eukaryotes. CtpA is distinctive by virtue of an N-terminal truncation in the domain responsible for cation binding. Growth of ctpA insertion mutants was restricted by the copper-chelating agent 8-hydroxyquinoline. DNA/RNA hybridisation studies revealed that levels of ctpA mRNA were increased following growth in media containing low and high copper concentrations. These results suggest the isolation of a region of DNA that encodes a novel copper-transporting system in L. monocytogenes.

Adenosine Triphosphatases↗

PubMed2001

The molecular basis of copper-transport diseases.

Copper (Cu) is a potentially toxic yet essential element. MENKES DISEASE, a copper deficiency disorder, and WILSON DISEASE, a copper toxicosis condition, are two human genetic disorders, caused by mutations of two closely related Cu-transporting ATPases. Both molecules efflux copper from cells. Quite diverse clinical phenotypes are produced by different mutations of these two Cu-transporting proteins. The understanding of copper homeostasis has become increasingly important in clinical medicine as the metal could be involved in the pathogenesis of some important neurological disorders such as Alzheimer's disease, motor neurone diseases and prion diseases.

Alzheimer Disease↗