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Defining the pathogenesis of the human ATP12p W94R mutation using a saccharomyces cerevisiae yeast model.

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Studies in yeast have shown that a deficiency in Atp12p prevents assembly of the extrinsic domain (F(1)) of Complex V and renders cells unable to make ATP through oxidative phosphorylation. De Meirleir et al. (J. Med. Genet., 41, 120-124, 2004) have reported that a homozygous missense mutation in the gene for human Atp12p (HuAtp12p), which replaces Trp94 with Arg, was linked to the death of a 14-month old patient. We have investigated the impact of the pathogenic W94R mutation on Atp12p structure/function. Plasmid-borne wild type human Atp12p rescues the respiratory defect of a yeast ATP12 deletion mutant (deltaatp12). The W94R mutation alters the protein at the most highly conserved position in the Pfam sequence, and renders HuAtp12p insoluble in the background of deltaatp12. In contrast, the yeast protein harboring the corresponding mutation, ScAtp12p(W103R), is soluble in the background of deltaatp12, but not in the background of deltaatp12deltafmc1, a strain that also lacks Fmc1p. Fmc1p is a yeast mitochondrial protein not found in higher eukaryotes. Tryptophan 94 (human) or 103 (yeast) is located in a positively charged region of Atp12p, and hence its mutation to arginine does not alter significantly the electrostatic properties of the protein. Instead, we provide evidence that the primary effect of the substitution is on the dynamic properties of Atp12p.
Tijdschrift: J. Biol. Chem.
ISSN: 0021-9258
Issue: February
Volume: 285
Pagina's: 4099-4109
Jaar van publicatie:2010
Trefwoorden:Atp12p, saccharomyces cerevisiae, yeast model, complex V deficiency
  • ORCID: /0000-0002-0853-9890/work/78128276
  • Scopus Id: 77950473492