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J. Biol. Chem., Vol. 281, Issue 18, 12270-12276, May 5, 2006

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The P174L Mutation in Human Sco1 Severely Compromises Cox17-dependent Metallation but Does Not Impair Copper Binding^*

Paul A. Cobine, Fabien Pierrel, Scot C. Leary¹, Florin Sasarman, Yih-Chern Horng, Eric A. Shoubridge², and Dennis R. Winge³

From the Departments of Medicine and Biochemistry, University of Utah Health Sciences Center, Salt Lake City, Utah 84132 and the Department of Human Genetics and Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada

Sco1 is a metallochaperone that is required for copper delivery to the Cu_A site in the CoxII subunit of cytochrome c oxidase. The only known missense mutation in human Sco1, a P174L substitution in the copper-binding domain, is associated with a fatal neonatal hepatopathy; however, the molecular basis for dysfunction of the protein is unknown. Immortalized fibroblasts from a SCO1 patient show a severe deficiency in cytochrome c oxidase activity that was partially rescued by overexpression of P174L Sco1. The mutant protein retained the ability to bind Cu(I) and Cu(II) normally when expressed in bacteria, but Cox17-mediated copper transfer was severely compromised both in vitro and in a yeast cytoplasmic assay. The corresponding P153L substitution in yeast Sco1 was impaired in suppressing the phenotype of cells harboring the weakly functional C57Y allele of Cox17; however, it was functional in sco1 yeast when the wild-type COX17 gene was present. Pulse-chase labeling of mitochondrial translation products in SCO1 patient fibroblasts showed no change in the rate of CoxII translation, but there was a specific and rapid turnover of CoxII protein in the chase. These data indicate that the P174L mutation attenuates a transient interaction with Cox17 that is necessary for copper transfer. They further suggest that defective Cox17-mediated copper metallation of Sco1, as well as the subsequent failure of Cu_A site maturation, is the basis for the inefficient assembly of the cytochrome c oxidase complex in SCO1 patients.

Received for publication, January 17, 2006 , and in revised form, February 22, 2006.

^* This work was supported by Grant ES 03817 from NIEH, National Institutes of Health (to D. R. W.) and by grants from the Muscular Dystrophy Association and the Canadian Institutes of Health Research (CIHR) (to E. A. S.). 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.

¹ Recipient of a postdoctoral fellowship from the CIHR.

² An International Scholar of the Howard Hughes Medical Institute and a senior investigator of the CIHR. To whom correspondence may be addressed: Dept. of Human Genetics and Montreal Neurological Institute of McGill University, 3801 University St., Rm. 660, Montreal, Quebec H3A 2B4, Canada. Tel: 514–398-1997; Fax: 514–398-1509; E-mail: eric{at}ericpc.mni.mcgill.ca. ³To whom correspondence may be addressed: University of Utah Health Sciences Center, Salt Lake City, UT 84132. Tel.: 801-585-5103; Fax: 801-585-5469; E-mail: dennis.winge{at}hsc.utah.edu.

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