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J. Biol. Chem., Vol. 279, Issue 7, 5072-5080, February 13, 2004

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Cox17 Is Functional When Tethered to the Mitochondrial Inner Membrane^*

Andrew B. Maxfield, Daren N. Heaton, and Dennis R. Winge¶

From the University of Utah Health Sciences Center, Salt Lake City, Utah 84132 and Brigham Young University, Hawaii 96762

Cox17 is an essential protein in the assembly of cytochrome c oxidase within the mitochondrion. Cox17 is implicated in providing copper ions for formation of Cu_A and Cu_B sites in the oxidase complex. To address whether Cox17 is functional in shuttling copper ions to the mitochondrion, Cox17 was tethered to the mitochondrial inner membrane by a fusion to the transmembrane domain of the inner membrane protein, Sco2. The copper-binding domain of Sco2 that projects into the inter-mitochondrial membrane space was replaced with Cox17. The Sco2/Cox17 fusion protein containing the mitochondrial import sequence and transmembrane segment of Sco2 is exclusively localized within the mitochondrion. The Sco2/Cox17 protein restores respiratory growth and normal cytochrome oxidase activity in cox17 cells. These studies suggest that the function of Cox17 is confined to the mitochondrial intermembrane space. Domain mapping of yeast Cox17 reveals that the carboxyl-terminal segment of the protein has a function within the intermembrane space that is independent of copper ion binding. The essential C-terminal function of Cox17 maps to a candidate amphipathic helix that is important for mitochondrial uptake and retention of the Cox17 protein. This motif can be spatially separated from the N-terminal copper-binding functional motif. Possible roles of the C-terminal motif are discussed.

Received for publication, October 27, 2003 , and in revised form, November 11, 2003.

^* This work was supported by Grant ES 03817 from the National Institutes of Environmental Health Sciences, National Institutes of Health (to D. R. W.), National Institutes of Health Grant 5P30-CA 42014 (to the Biotechnology Core Facility for DNA synthesis at the University of Utah), and by Grant T32 DK07115 from the National Institutes of Health (to A. B. M.). 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.

^¶ To whom correspondence should be addressed. Tel.: 801-585-5103; Fax: 801-585-5469; E-mail: dennis.winge{at}hsc.utah.edu.

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