The P174L mutation in human Sco1 severely compromises Cox17-dependent metallation but does not impair copper binding

Paul A. Cobine, Fabien Pierrel, Scot C. Leary, Florin Sasarman, Yih Chern Horng, Eric A. Shoubridge, Dennis R. Winge

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30 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)12270-12276
Number of pages7
JournalJournal of Biological Chemistry
Issue number18
Publication statusPublished - 2006 May 5

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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