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http://ir.ncue.edu.tw/ir/handle/987654321/15151
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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
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| Issue Date: | 2013-01-07T02:15:53Z
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| 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 |
| Appears in Collections: | [化學系] 期刊論文
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