title: Mammalian copper chaperone Cox17p has an essential role in activation of cytochrome C oxidase and embryonic development.
abstract: Cox17p is essential for the assembly of functional cytochrome c oxidase (CCO) and for delivery of copper ions to the mitochondrion for insertion into the enzyme in yeast. Although this small protein has already been cloned or purified from humans, mice, and pigs, the function of Cox17p in the mammalian system has not yet been elucidated. In vitro biochemical data for mammalian Cox17p indicate that the copper binds to the sequence -KPCCAC-. Although mouse embryos homozygous for COX17 disruption die between embryonic days E8.5 and E10, they develop normally until E6.5. This phenotype is strikingly similar to embryos of Ctr1(-/-), a cell surface copper transporter, in its lethality around the time of gastrulation. COX17-deficient embryos exhibit severe reductions in CCO activity at E6.5. Succinate dehydrogenase activity and immunoreactivities for anti-COX subunit antibodies were normal in the COX17(-/-) embryos, indicating that this defect was not caused by the deficiency of other complexes and/or subunits but was caused by impaired CCO activation by Cox17p. Since other copper chaperone (Atox1 and CCS)-deficient mice show a more moderate defect, the disruption of the COX17 locus causes the expression of only the phenotype of Ctr1(-/-). We found that the activity of lactate dehydrogenase was also normal in E6.5 embryos, implying that the activation of CCO by Cox17p may not be essential to the progress of embryogenesis before gastrulation.
authors.affiliation: Institute of Applied Biochemistry, University of Tsukuba, Tsukuba 305-8572, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kako
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Kashiwabara
authors.forename: Akio
authors.initials: A
authors.lastname: Takehara
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Inada
authors.forename: Hidenori
authors.initials: H
authors.lastname: Arai
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nakada
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kodama
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Hayashi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Baba
authors.forename: Eisuke
authors.initials: E
authors.lastname: Munekata
mesh_terms: D000483:Alleles; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism* / Q000502:physiology*; D003300:Copper / Q000378:metabolism; D000079922:Copper Transport Proteins; D018076:DNA, Complementary / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism; D004789:Enzyme Activation; D005838:Genotype; D005982:Glutathione Transferase / Q000378:metabolism; D006579:Heterozygote; D007150:Immunohistochemistry; D051379:Mice; D008957:Models, Genetic; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: C100359:COX17 protein, S cerevisiae; D027682:Cation Transport Proteins; D000079922:Copper Transport Proteins; C491005:Cox17 protein, mouse; D018076:DNA, Complementary; D018832:Molecular Chaperones; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D003300:Copper; D003576:Electron Transport Complex IV; D005982:Glutathione Transferase