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Gene Review

COX17  -  copper metallochaperone COX17

Saccharomyces cerevisiae S288c

Synonyms: Cytochrome c oxidase copper chaperone, L1343, YLL009C
 
 
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Disease relevance of COX17

  • We have characterized the respiration-deficient cox17 mutants and found in addition to the expected cytochrome oxidase deficiency, a specific lack of Cox2p and the presence of a misassembled cytochrome oxidase in a subset of mutants [1].
  • Identification of COX17 as a therapeutic target for non-small cell lung cancer [2].
 

High impact information on COX17

  • Puf3p also binds to the COX17 mRNA 3'-UTR in vitro [3].
  • 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(-/-) [4].
  • 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 [4].
  • Because our data imply that up-regulation of COX17 function and increased CCO activity are frequent features of lung carcinogenesis, we suggest that selective suppression of components of the CCO complex might hold promise for development of a new strategy for treating lung cancers [2].
  • By semiquantitative reverse transcription-PCR, we documented increased expression of COX17 in all of 8 primary NSCLCs and in 11 of 15 NSCLC cell lines examined, by comparison with normal lung tissue [2].
 

Biological context of COX17

  • In contrast, neither copper, COX17 on a multicopy plasmid, or a combination of the two is able to restore respiration in sco1 mutants [5].
  • Overexpression of Cox17p by itself is not a sufficient condition to rescue the mutant phenotype [6].
  • Rescue of cox17 mutants by Sco1p suggests that this mitochondrial protein plays a role either in mitochondrial copper transport or insertion of copper into the active site of cytochrome oxidase [5].
  • We have identified a new plant gene, AtCOX17, encoding a protein that shares sequence similarity to COX17, a Cu-binding protein from yeast (Saccharomyces cerevisiae) and vertebrates that mediates the delivery of Cu to the mitochondria for the assembly of a functional cytochrome oxidase complex [7].
  • In vivo, presence of either site partially stimulates COX17 mRNA decay, but full decay regulation requires the presence of both sites [8].
 

Anatomical context of COX17

  • Cox23p, like Cox17p, is detected in the intermembrane space of mitochondria and in the postmitochondrial supernatant fraction, the latter consisting predominantly of cytosolic proteins [6].
 

Associations of COX17 with chemical compounds

  • Yeast cox17 solution structure and Copper(I) binding [9].
  • COX17 was originally cloned by virtue of complementation of a mutant containing a nonfunctional Cys --> Tyr substitution at codon 57 [10].
  • Subcloning and sequencing of the COX17 gene revealed that it codes for a cysteine-rich protein with a molecular weight of 8,057 [11].
  • The molar copper content is increased to 1.8 after incubation of Cox17p in the presence of a 6-fold molar excess of cuprous chloride under reduced conditions [12].
  • 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 [13].
 

Regulatory relationships of COX17

  • In the present study COX17 has been placed under the control of the GAL10 promoter in an autonomously replicating plasmid [12].
  • Here we study the mechanism by which the yeast Puf3p binds and stimulates the degradation of COX17 mRNA [14].
 

Other interactions of COX17

  • Although SCO2 can also partially restore respiratory growth in the cox17 null mutant, rescue in this case requires addition of copper to the growth medium [5].
  • C129/U1 is a respiratory defective mutant of Saccharomyces cerevisiae arrested in cytochrome oxidase assembly due to a mutation in COX17, a nuclear gene encoding a low molecular weight cytoplasmic protein proposed to function in mitochondrial copper recruitment [5].
  • Examination of COX17 mRNA indicates that Puf3p specifically promotes decay of this mRNA by enhancing the rate of deadenylation and subsequent turnover [3].
  • Orthologues of the three copper chaperones characterized in yeast, ATX1, CCS and COX17, are present in Arabidopsis thaliana [15].
  • Specific copper transfer from the Cox17 metallochaperone to both Sco1 and Cox11 in the assembly of yeast cytochrome C oxidase [16].
 

Analytical, diagnostic and therapeutic context of COX17

  • According to isothermal titration calorimetry experiments, fully reduced Cox17 binds one Cu(I) ion with a K(a) of (6.15 +/- 5.83) x 10(6) M(-1) [9].
  • Given the small size of Cox17p, we have taken a random and site-directed mutagenesis approach to studying structure-function relationships in Cox17p [1].

References

  1. Mutagenesis reveals a specific role for Cox17p in copper transport to cytochrome oxidase. Punter, F.A., Glerum, D.M. J. Biol. Chem. (2003) [Pubmed]
  2. Identification of COX17 as a therapeutic target for non-small cell lung cancer. Suzuki, C., Daigo, Y., Kikuchi, T., Katagiri, T., Nakamura, Y. Cancer Res. (2003) [Pubmed]
  3. The Puf3 protein is a transcript-specific regulator of mRNA degradation in yeast. Olivas, W., Parker, R. EMBO J. (2000) [Pubmed]
  4. Mammalian copper chaperone Cox17p has an essential role in activation of cytochrome C oxidase and embryonic development. Takahashi, Y., Kako, K., Kashiwabara, S., Takehara, A., Inada, Y., Arai, H., Nakada, K., Kodama, H., Hayashi, J., Baba, T., Munekata, E. Mol. Cell. Biol. (2002) [Pubmed]
  5. SCO1 and SCO2 act as high copy suppressors of a mitochondrial copper recruitment defect in Saccharomyces cerevisiae. Glerum, D.M., Shtanko, A., Tzagoloff, A. J. Biol. Chem. (1996) [Pubmed]
  6. COX23, a homologue of COX17, is required for cytochrome oxidase assembly. Barros, M.H., Johnson, A., Tzagoloff, A. J. Biol. Chem. (2004) [Pubmed]
  7. AtCOX17, an Arabidopsis homolog of the yeast copper chaperone COX17. Balandin, T., Castresana, C. Plant Physiol. (2002) [Pubmed]
  8. Recruitment of the Puf3 protein to its mRNA target for regulation of mRNA decay in yeast. Jackson, J.S., Houshmandi, S.S., Lopez Leban, F., Olivas, W.M. RNA (2004) [Pubmed]
  9. Yeast cox17 solution structure and Copper(I) binding. Abajian, C., Yatsunyk, L.A., Ramirez, B.E., Rosenzweig, A.C. J. Biol. Chem. (2004) [Pubmed]
  10. Mutational analysis of the mitochondrial copper metallochaperone Cox17. Heaton, D., Nittis, T., Srinivasan, C., Winge, D.R. J. Biol. Chem. (2000) [Pubmed]
  11. Characterization of COX17, a yeast gene involved in copper metabolism and assembly of cytochrome oxidase. Glerum, D.M., Shtanko, A., Tzagoloff, A. J. Biol. Chem. (1996) [Pubmed]
  12. Purification, characterization, and localization of yeast Cox17p, a mitochondrial copper shuttle. Beers, J., Glerum, D.M., Tzagoloff, A. J. Biol. Chem. (1997) [Pubmed]
  13. The P174L Mutation in Human Sco1 Severely Compromises Cox17-dependent Metallation but Does Not Impair Copper Binding. Cobine, P.A., Pierrel, F., Leary, S.C., Sasarman, F., Horng, Y.C., Shoubridge, E.A., Winge, D.R. J. Biol. Chem. (2006) [Pubmed]
  14. Yeast Puf3 mutants reveal the complexity of Puf-RNA binding and identify a loop required for regulation of mRNA decay. Houshmandi, S.S., Olivas, W.M. RNA (2005) [Pubmed]
  15. Plant copper chaperones. Wintz, H., Vulpe, C. Biochem. Soc. Trans. (2002) [Pubmed]
  16. Specific copper transfer from the Cox17 metallochaperone to both Sco1 and Cox11 in the assembly of yeast cytochrome C oxidase. Horng, Y.C., Cobine, P.A., Maxfield, A.B., Carr, H.S., Winge, D.R. J. Biol. Chem. (2004) [Pubmed]
 
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