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J. Biol. Chem., Vol. 279, Issue 52, 54221-54229, December 24, 2004

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Mobilization of Intracellular Copper Stores by the Ctr2 Vacuolar Copper Transporter^*

Erin M. Rees, Jaekwon Lee, and Dennis J. Thiele¶

From the Department of Pharmacology and Cancer Biology, and the Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina 27710 and the Department of Biochemistry, University of Nebraska, Lincoln, Nebraska 68588

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 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.

Received for publication, October 13, 2004

^* This work was supported by National Institutes of Health Grants GM41840 (to D. J. T.) and P20 RR-17675 (to J. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Figs. S1 and S2.

^¶ To whom correspondence should be addressed. Tel.: 919-684-5776; Fax: 919-668-6044; E-mail: dennis.thiele{at}duke.edu.

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