Essential Roles in Development and Pigmentation for the Drosophila Copper Transporter DmATP7 (original) (raw)
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The International Journal of Biochemistry & Cell Biology, 2008
Copper homeostasis is achieved by a combination of regulated uptake, efflux and sequestration and is essential for animal health and viability. Transmembrane copper transport proteins of the P-type ATPase family play key roles in cellular copper efflux. Here, the transcriptional and post-translational regulation of DmATP7, the sole Drosophila melanogaster ortholog of the human MNK and WND copper transport genes, is examined. An enhancer element with sufficient regulatory information to rescue DmATP7 mutant flies to adulthood is identified. This regulatory element drives expression in all neuronal tissues examined and demonstrates copper-inducible, Mtf-1 dependent expression in the larval midgut. These results support an important functional role for copper transport in neuronal tissues and indicate that regulation of DmATP7 expression is not used to limit copper absorption in toxic copper conditions. Localisation of a functional EYFP-DmATP7 fusion protein is also examined. This fusion protein localises at or proximal to the basolateral membrane of DmATP7 expressing midgut cells supporting a role for DmATP7 in export of copper from midgut cells.
Molecular genetics of intracellular copper transport
The Journal of Trace Elements in Experimental Medicine, 1999
Copper is essential for life processes as cofactor for many vital cuproenzymes, yet it is extremely toxic in excess. Efficient mechanisms have been developed to recruit and deliver copper to enzymes and for excretion of surplus metal. Imbalance of copper homeostasis is manifested in two human illnesses, Menkes disease and Wilson disease, which are both caused by defective export mechanisms that involve ATP7A and ATP7B, respectively. Severe deficiency of copper is mimicked by Menkes disease, whereas Wilson disease leads to toxic accumulations of the metal. The copper export pumps are energy requiring transporters possessing a number of unique molecular features. Besides domains typical for P-type ATPases, several heavy metal specific sites have been described in the copper subfamily of the ATPases. Identification of disease-causing mutations will help to define structural determinants of normal copper pump function. In this review we discuss the current knowledge about the human copper pumps, ATP7A and its homologue ATP7B. J.
Genes regulating copper metabolism
Molecular and Cellular Biochemistry, 1998
The metabolism of Cu is intimately linked with its nutrition. From gut to enzymes, Cu bioavailability to key enzymes and other components operates through a complex mechanism that uses transport proteins as well as small molecular weight ligands.
Molecular and cellular aspects of copper transport in developing mammals
The Journal of nutrition, 2003
Copper is an essential trace element that requires tightly regulated homeostatic mechanisms to ensure adequate supplies without any toxic effects because of the ability of the metal ion to catalyze the formation of free radicals. The Cu-ATPases, ATP7A and ATP7B, play an important role in the physiological regulation of copper. Adequate supplies of copper are particularly important in developing animals, and in humans this is illustrated by mutations of ATP7A that cause the copper deficiency condition Menkes disease, which is fatal in early childhood. In contrast, mutations in ATP7B result in the genetic toxicosis, Wilson disease. We propose that the physiological regulation of copper is accomplished mainly by the intracellular copper-regulated trafficking of the Cu-ATPases. This process allows the overall copper status in the body to be maintained when levels of copper in the diet alter. A study of the defects in mouse models of Menkes and Wilson diseases has demonstrated that both ...
Molecular mechanisms of copper metabolism and the role of the Menkes disease protein
Journal of Biochemical and Molecular Toxicology, 1999
Menkes disease is an X-linked, recessive disorder of copper metabolism that occurs in approximately 1 in 200,000 live births. The condition is characterized by skeletal abnormalities, severe mental retardation, neurologic degeneration, and patient mortality in early childhood. The symptoms of Menkes disease result from a deficiency of serum copper and copper-dependent enzymes. A candidate gene for the disease has been isolated and designated MNK.
Malvolio is a copper transporter in Drosophila melanogaster
Journal of Experimental Biology, 2008
Divalent metal ion transporter 1 (DMT1; also known as SLC11A2) can transport several metals including Fe and Cu in mammalian systems. We set out to determine whether Malvolio (Mvl), the Drosophila melanogaster orthologue of DMT1, can also transport Cu. Overexpression of Mvl caused Cu accumulation in Drosophila S2 cultured cells and conversely dsRNAi knockdown of endogenous Mvl reduced cellular Cu levels. Cell viability under Cu limiting conditions was reduced following dsRNAi knockdown. A homozygous viable Mvl loss-of-function mutant (Mvl 97f ) was sensitive to excess Cu and female Mvl 97f flies were also sensitive to Cu limitation. An MtnA-EYFP reporter was used as a proxy measure of Cu distribution within Mvl 97f/+ larvae. Under basal conditions Cu levels were reduced in the anterior midgut and proventriculus relative to control larvae. These results demonstrate Mvl is a functional Cu transporter and that despite partial functional redundancy with the Ctr1 proteins, Cu uptake through this pathway is necessary for optimal viability at the cellular and organismal levels.
Annals of the New York Academy of Sciences, 2014
Copper is an important cofactor in numerous biological processes in all living organisms. However, excessive copper can be extremely toxic, so it is vital that the copper level within a cell is tightly regulated. The damaging effect of copper is seen in several hereditary forms of copper toxicity in humans and animals. At present, Wilson's disease is the best-described and best-studied copper-storage disorder in humans; it is caused by mutations in the ATP7B gene. In dogs, a mutation in the COMMD1 gene has been found to be associated with copper toxicosis. Using a liver-specific Commd1 knockout mouse, the biological role of Commd1 in copper homeostasis has been confirmed. Yet, the exact mechanism by which COMMD1 regulates copper homeostasis is still unknown. Here, we give an overview of the current knowledge and perspectives on the molecular function of COMMD1 in copper homeostasis.
Trafficking of the copper-ATPases, ATP7A and ATP7B: Role in copper homeostasis
Archives of Biochemistry and Biophysics, 2007
Copper is essential for human health and copper imbalance is a key factor in the aetiology and pathology of several neurodegenerative diseases. The copper-transporting P-type ATPases, ATP7A and ATP7B are key molecules required for the regulation and maintenance of mammalian copper homeostasis. Their absence or malfunction leads to the genetically inherited disorders, Menkes and Wilson diseases, respectively. These proteins have a dual role in cells, namely to provide copper to essential cuproenzymes and to mediate the excretion of excess intracellular copper. A unique feature of ATP7A and ATP7B that is integral to these functions is their ability to sense and respond to intracellular copper levels, the latter manifested through their copper-regulated trafficking from the transGolgi network to the appropriate cellular membrane domain (basolateral or apical, respectively) to eliminate excess copper from the cell. Research over the last decade has yielded significant insight into the enzymatic properties and cell biology of the copper-ATPases. With recent advances in elucidating their localization and trafficking in human and animal tissues in response to physiological stimuli, we are progressing rapidly towards an integrated understanding of their physiological significance at the level of the whole animal. This knowledge in turn is helping to clarify the biochemical and cellular basis not only for the phenotypes conferred by individual Menkes and Wilson disease patient mutations, but also for the clinical variability of phenotypes associated with each of these diseases. Importantly, this information is also providing a rational basis for the applicability and appropriateness of certain diagnostic markers and therapeutic regimes. This overview will provide an update on the current state of our understanding of the localization and trafficking properties of the copper-ATPases in cells and tissues, the molecular signals and posttranslational interactions that govern their trafficking activities, and the cellular basis for the clinical phenotypes associated with disease-causing mutations.
Syntaxin 5 Is Required for Copper Homeostasis in Drosophila and Mammals
PLoS ONE, 2010
Copper is essential for aerobic life, but many aspects of its cellular uptake and distribution remain to be fully elucidated. A genome-wide screen for copper homeostasis genes in Drosophila melanogaster identified the SNARE gene Syntaxin 5 (Syx5) as playing an important role in copper regulation; flies heterozygous for a null mutation in Syx5 display increased tolerance to high dietary copper. The phenotype is shown here to be due to a decrease in copper accumulation, a mechanism also observed in both Drosophila and human cell lines. Studies in adult Drosophila tissue suggest that very low levels of Syx5 result in neuronal defects and lethality, and increased levels also generate neuronal defects. In contrast, mild suppression generates a phenotype typical of copper-deficiency in viable, fertile flies and is exacerbated by co-suppression of the copper uptake gene Ctr1A. Reduced copper uptake appears to be due to reduced levels at the plasma membrane of the copper uptake transporter, Ctr1. Thus Syx5 plays an essential role in copper homeostasis and is a candidate gene for copper-related disease in humans.