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

The Journal of Biological Chemistry
Paul A CobineDennis R Winge

Abstract

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 sco1delta 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 i...Continue Reading

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Citations

Apr 9, 2008·The Journal of Biological Chemistry·Kevin RigbyDennis R Winge
Apr 2, 2009·Human Molecular Genetics·Scot C LearyEric A Shoubridge
Sep 6, 2012·Acta Crystallographica. Section D, Biological Crystallography·Luciano A Abriata
Mar 9, 2010·Annual Review of Biochemistry·Nigel J Robinson, Dennis R Winge
Dec 22, 2006·Proceedings of the National Academy of Sciences of the United States of America·Lucia BanciShenlin Wang
Sep 10, 2015·Proceedings of the National Academy of Sciences of the United States of America·Marcos N MorgadaAlejandro J Vila
Apr 27, 2011·The FEBS Journal·Lucia BanciSimone Ciofi-Baffoni
Jul 24, 2013·Human Mutation·Scot C LearyEric A Shoubridge
Jun 5, 2008·Biochimica Et Biophysica Acta·Scot C LearyPaul A Cobine
Apr 20, 2010·Biochimica Et Biophysica Acta·Lukas Stiburek, Jiri Zeman
Sep 28, 2017·Metallomics : Integrated Biometal Science·Zakery N BakerScot C Leary
Jul 5, 2008·Expert Review of Molecular Diagnostics·Gabriele SicilianoLuigi Murri
Mar 20, 2009·American Journal of Physiology. Cell Physiology·Lukas StiburekJiri Zeman
Jun 23, 2009·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Samantha J DaintyNigel J Robinson
Mar 7, 2007·Journal of Proteome Research·Aalt D J van DijkAlexandre M J J Bonvin

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