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J. Biol. Chem., Vol. 280, Issue 31, 28811-28818, August 5, 2005

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Heteromeric Protein Complexes Mediate Zinc Transport into the Secretory Pathway of Eukaryotic Cells^*

Charissa D. Ellis, Colin W. MacDiarmid, and David J. Eide¶

From the Department of Nutritional Sciences, University of Wisconsin, Madison, Wisconsin 53706

The cation diffusion facilitator (CDF) family of metal ion transporters plays important roles in zinc transport at all phylogenetic levels. In this report, we describe a novel interaction between two members of the CDF family in Saccharomyces cerevisiae. One CDF member in yeast, Msc2p, was shown recently to be involved in zinc transport into the endoplasmic reticulum (ER) and required for ER function. We describe here a newly recognized CDF family member in yeast, Zrg17p. ZRG17 was previously identified as a zinc-regulated gene controlled by the zinc-responsive Zap1p transcription factor. A zrg17 mutant exhibits the same zinc-suppressible phenotypes as an msc2 mutant, including an induction of the unfolded protein response in low zinc. Moreover, a significant fraction of the total Zrg17p protein appears to localize to the ER. Their common phenotypes and localization suggested that these two proteins function together to mediate zinc transport into the ER. Consistent with this hypothesis, Msc2p and Zrg17p physically interact with each other, as determined by co-immunoprecipitation. Therefore, we propose that Msc2p and Zrg17p form a heteromeric zinc transport complex in the ER membrane. We also demonstrate that ZnT5 and ZnT6, mammalian homologues of Msc2p and Zrg17p, functionally interact as well. These results suggest that heteromeric complexes formed by different CDF members may be a common phenomenon for this ubiquitous family of metal ion transporters.

Received for publication, May 19, 2005 , and in revised form, June 14, 2005.

^* This work was supported by National Institutes of Health (NIH) Grants GM56285 and GM69786. 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.

Supported by NIH Predoctoral Training Grant GM08396 and Postdoctoral Training Grant DK07665.

Present address: Dept. of Biology, University of Missouri, St. Louis, MO 63121.

^¶ To whom correspondence should be addressed: Dept. of Nutritional Sciences, University of Wisconsin, 1415 Linden Dr., Rm. 340B, Madison, WI 53706. Tel.: 608-263-1613; Fax: 608-262-5860; E-mail: eide{at}nutrisci.wisc.edu.

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