Mobilization of Intracellular Copper Stores by the Ctr2 Vacuolar Copper Transporter

Rees, Erin M.; Lee, Jaekwon; Thiele, Dennis J.

doi:10.1074/jbc.m411669200

Cited by 181 publications

(205 citation statements)

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“…extremely limiting or abnormally abundant (29). At present, little is known regarding the function of Ctr1C in Drosophila although one possibility, based on the observation that overexpression of Ctr1C in S2 cells does not mediate copper uptake (29), is that Ctr1C may function on an intracellular compartment and in that regard may be more similar to S. cerevisiae Ctr2 (54). However, further experiments will be necessary to ascertain the contributions of Drosophila Ctr1C to total body copper homeostasis and to determine whether it is an ortholog of S. cerevisiae Ctr2.…”

Section: Discussionmentioning

confidence: 99%

Drosophila Ctr1A Functions as a Copper Transporter Essential for Development

Turski¹,

Thiele

2007

Journal of Biological Chemistry

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Copper is an essential trace element required by all aerobic organisms as a cofactor for enzymes involved in normal growth, development, and physiology. Ctr1 proteins are members of a highly conserved family of copper importers responsible for copper uptake across the plasma membrane. Mice lacking Ctr1 die during embryogenesis from widespread developmental defects, demonstrating the need for adequate copper acquisition in the development of metazoan organisms via as yet uncharacterized mechanisms. Whereas the fruit fly, Drosophila melanogaster, expresses three Ctr1 genes, ctr1A, ctr1B, and ctr1C, little is known about their protein isoform-specific roles. Previous studies demonstrated that Ctr1B localizes to the plasma membrane and is not essential for development unless flies are severely copper-deficient or are subjected to copper toxicity. Here we demonstrate that Ctr1A also resides on the plasma membrane and is the primary Drosophila copper transporter. Loss of Ctr1A results in copper-remedial developmental arrest at early larval stages. Ctr1A mutants are deficient in the activity of copper-dependent enzymes, including cytochrome c oxidase and tyrosinase. Amidation of Phe-Met-Arg-Pheamides, a group of cardiomodulatory neuropeptide hormones that are matured via the action of peptidylglycine ␣-hydroxylating monooxygenase, is defective in neuroendocrine cells of Ctr1A mutant larvae. Moreover, both the Phe-Met-Arg-Pheamide maturation and heart beat rate defects observed in Ctr1A mutant larvae can be partially rescued by exogenous copper. These studies establish clear physiological distinctions between two Drosophila plasma membrane copper transport proteins and demonstrate that copper import by Ctr1A is required to drive neuropeptide maturation during normal growth and development.

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Section: Discussionmentioning

confidence: 99%

Drosophila Ctr1A Functions as a Copper Transporter Essential for Development

Turski¹,

Thiele

2007

Journal of Biological Chemistry

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“…Although previous results indicate that the Arabidopsis COPT1 protein could function in Cu acquisition in the plasma membrane of specific plant cells (Kampfenkel et al, 1995;Sancenon et al, 2003Sancenon et al, , 2004, the fact that certain CTR members are located at intracellular endosomal vesicles or vacuolar membranes in other eukaryotic organisms (Bellemare et al, 2002;Rees et al, 2004;van den Berghe et al, 2007;Bertinato et al, 2008) prompted us to address the subcellular localization of COPT1 in Arabidopsis cells. To that end, the coding sequence of the COPT1 protein was fused to GFP (COPT1-GFP) under the control of the constitutive cauliflower mosaic virus (CaMV) 35S promoter.…”

Section: The Copt1 Cu Transport Protein Localizes To the Plasma Membrmentioning

confidence: 99%

Deregulated Copper Transport Affects Arabidopsis Development Especially in the Absence of Environmental Cycles

et al. 2010

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Copper is an essential cofactor for key processes in plants, but it exerts harmful effects when in excess. Previous work has shown that the Arabidopsis (Arabidopsis thaliana) COPT1 high-affinity copper transport protein participates in copper uptake through plant root tips. Here, we show that COPT1 protein localizes to the plasma membrane of Arabidopsis cells and the phenotypic effects of transgenic plants overexpressing either COPT1 or COPT3, the latter being another high-affinity copper transport protein family member. Both transgenic lines exhibit increased endogenous copper levels and are sensitive to the copper in the growth medium. Additional phenotypes include decreased hypocotyl growth in red light and differentially affected flowering times depending on the photoperiod. Furthermore, in the absence of environmental cycles, such as light and temperature, the survival of plants overexpressing COPT1 or COPT3 is compromised. Consistent with altered circadian rhythms, the expression of the nuclear circadian clock genes CIRCADIAN CLOCK-ASSOCIATED1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY) is substantially reduced in either COPT1-or COPT3-overexpressing plants. Copper affects the amplitude and the phase, but not the period, of the CCA1 and LHY oscillations in wild-type plants. Copper also drives a reduction in the expression of circadian clock output genes. These results reveal that the spatiotemporal control of copper transport is a key aspect of metal homeostasis that is required for Arabidopsis fitness, especially in the absence of environmental cues.

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“…Previous studies suggest that, similar to Ctr1, the S. cerevisiae Ctr2 protein has three transmembrane domains, exists as a homomultimer, and resides in the vacuolar membrane where it serves to mobilize vacuolar copper stores to cytosolic copper chaperones (28,29). Although Ctr2 requires the conserved methionine residues in the amino terminus and second transmembrane domain for copper mobilization, it is has not been established whether Ctr2 transports Cu(I) and, if so, whether vacuolar copper mobilization involves a metalloreductase.…”

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Identification of a Vacuole-associated Metalloreductase and Its Role in Ctr2-mediated Intracellular Copper Mobilization

Rees

Thiele

2007

Journal of Biological Chemistry

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Copper is an essential trace metal whose biological utility is derived from its ability to cycle between oxidized Cu(II) and reduced Cu(I). Ctr1 is a high affinity plasma membrane copper permease, conserved from yeast to humans, that mediates the physiological uptake of Cu(I) from the extracellular environment. In the baker's yeast Saccharomyces cerevisiae, extracellular Cu(II) is reduced to Cu(I) via the action of the cell surface metalloreductase Fre1, similar to the human gp91 phox subunit of the NADPH oxidase complex, which utilizes heme and flavins to catalyze electron transfer. The S. cerevisiae Ctr2 protein is structurally similar to Ctr1, localizes to the vacuole membrane, and mobilizes vacuolar copper stores to the cytosol via a mechanism that is not well understood. Here we show that Ctr2-1, a mutant form of Ctr2 that mislocalizes to the plasma membrane, requires the Fre1 plasma membrane metalloreductase for Cu(I) import. The conserved methionine residues that are essential for Ctr1 function at the plasma membrane are also essential for Ctr2-1-mediated Cu(I) uptake. We demonstrate that Fre6, a member of the yeast Fre1 metalloreductase protein family, resides on the vacuole membrane and functions in Ctr2-mediated vacuolar copper export, and cells lacking Fre6 phenocopy the Cu-deficient growth defect of ctr2⌬ cells. Furthermore, both CTR2 and FRE6 mRNA levels are regulated by iron availability. Taken together these studies suggest that copper movement across intracellular membranes is mechanistically similar to that at the plasma membrane. This work provides a model for communication between the extracellular Cu(I) uptake and the intracellular Cu(I) mobilization machinery.

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Mobilization of Intracellular Copper Stores by the Ctr2 Vacuolar Copper Transporter

Cited by 181 publications

References 57 publications

Drosophila Ctr1A Functions as a Copper Transporter Essential for Development

Drosophila Ctr1A Functions as a Copper Transporter Essential for Development

Deregulated Copper Transport Affects Arabidopsis Development Especially in the Absence of Environmental Cycles

Identification of a Vacuole-associated Metalloreductase and Its Role in Ctr2-mediated Intracellular Copper Mobilization

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