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Title: The P174L Mutation in Human Sco1 Severely Compromises Cox17-dependent Metallation but Does Not Impair Copper Binding
Authors: Cobine, Paul A.;Pierrel, Fabien;Leary, Scot C.;Sasarman, Florin;Horng, Yih-Chern;Shoubridge, Eric A.;Winge, Dennis R.
Contributors: 化學系
Date: 2006
Issue Date: 2013-01-07T02:15:53Z
Publisher: American Society for Biochemistry and Molecular Biology
Abstract: Sco1 is a metallochaperone that is required for copper delivery to the CuA 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 sco1Δ 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 CuA site maturation, is the basis for the inefficient assembly of the cytochrome c oxidase complex in SCO1 patients.
Relation: J. Biol. Chem., 281: 12270-12276
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