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COX2  -  cytochrome c oxidase subunit 2

Saccharomyces cerevisiae S288c

Synonyms: Cytochrome c oxidase polypeptide II, Cytochrome c oxidase subunit 2, OXI1, OXII, Q0250
 
 
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Disease relevance of COX2

  • 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].
 

High impact information on COX2

  • Accumulation of mitochondrially synthesized Saccharomyces cerevisiae Cox2p and Cox3p depends on targeting information in untranslated portions of their mRNAs [2].
  • We have identified a spontaneous mitochondrial mutation, mfs-1 (mitochondrial frameshift suppressor-1), which suppresses a + 1 frameshift mutation localized in the yeast mitochondrial oxi1 gene [3].
  • The mitochondrial gene oxi1, carried on a bacterial plasmid, has been used to transform the mitochondria of a yeast strain lacking mtDNA (rho0) [4].
  • The Saccharomyces cerevisiae nuclear gene MSS2 was previously shown to be necessary for Cox2p accumulation [5].
  • Mutational inactivation of the proteolytic function of the matrix-localized Yta10p (Afg3p) AAA-protease partially stabilizes Cox2p in an mss2 mutant but does not restore assembly of cytochrome oxidase [5].
 

Biological context of COX2

  • We also found that Pet111p is present at levels limiting the synthesis of Cox2p by examining the effect of altered PET111 gene dosage in the nucleus on expression of a reporter gene, cox2::ARG8(m), that was inserted into mitochondrial DNA [6].
  • Expression of mitochondrion-targeted T7Pol at high levels from the GAL1 promoter has no detectable effect on mitochondrial function in rho+ cells lacking the T7-COX2 target gene, but in cells with T7-COX2 integrated into the mitochondrial genome, an equivalent level of T7Pol expression causes severe respiratory deficiency [7].
  • In comparison with wild-type COX2 expression, steady-state levels of T7-COX2 mRNA increase fivefold when transcription is driven by T7Pol expressed from the ADH1 promoter, yet COXII protein levels and cellular respiration rates decrease by about 50% [7].
  • In vivo analysis of mutated initiation codons in the mitochondrial COX2 gene of Saccharomyces cerevisiae fused to the reporter gene ARG8m reveals lack of downstream reinitiation [8].
  • This is not a consequence of reduced membrane potential due to loss of cytochrome oxidase activity because Cox2p C-tail export was not blocked in mitochondria lacking Cox4p [9].
 

Anatomical context of COX2

  • Thus, Pet111p could play dual roles in both membrane localization and regulation of Cox2p synthesis within mitochondria [6].
  • The mitochondrial inner membrane peptidase Imp is required for proteolytic processing of the mitochondrially encoded protein Cox2, the nucleus-encoded Cyt b2, Mcr1, and Cyt c1, and possibly other proteins, during their transport across the mitochondrial membranes [10].
 

Associations of COX2 with chemical compounds

  • Substitution of Leu240 to serine in the protein results in an accumulation of the precursor form of the mitochondrially encoded subunit 2 of cytochrome oxidase (Cox2) and temperature-sensitive respiration [11].
  • The alteration, at residue 163 in the yeast polypeptide, substitutes isoleucine for threonine and leads to loss of Cox2p and loss of the ability to carry out cellular respiration [12].
  • This temperature sensitivity can be suppressed by a mutation in the cox2 gene changing Ala189 of the Cox2 protein to proline [11].
  • Abscisic acid and H(2)O(2) induction of AtLEA5 was also independent of the OXI1 protein kinase [13].
 

Physical interactions of COX2

 

Regulatory relationships of COX2

  • Complete deletion of RSM28 caused only a modest decrease in growth on nonfermentable carbon sources in otherwise wild-type strains and enhanced the respiratory defect of the suppressible cox2 mutations [16].
 

Other interactions of COX2

  • Although cells expressing these chimeric mRNAs actively synthesized both membrane proteins, they were severely deficient in cytochrome c oxidase activity and in the accumulation of Cox2p and Cox3p, respectively [2].
  • The synthesis of Cox1p and Cox3p in mutant mitochondria is normal whereas Cox2p is barely detected among labeled mitochondrial polypeptides [17].
  • In the absence of Oxa1p, the translocation of the mitochondrially encoded subunit Cox2p to the intermembrane space (also referred to as export) is prevented, and it has been proposed that Oxa1p could be a component of a general mitochondrial export machinery [18].
  • Focusing on Cox18p, we found that its activity is required to export the C-tail of Cox2p bearing a short C-terminal epitope tag [9].
  • The inner membrane proteins Mss2p and Pnt1p both coimmunoprecipitate with Cox18p, suggesting that they work together in translocation of Cox2p domains, an inference supported by functional interactions among the three genes [9].
 

Analytical, diagnostic and therapeutic context of COX2

  • Northern blots of wild type mitochondrial RNA were hybridized to single-stranded probes from the oxi1 gene and flanking regions [19].

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. Accumulation of mitochondrially synthesized Saccharomyces cerevisiae Cox2p and Cox3p depends on targeting information in untranslated portions of their mRNAs. Sanchirico, M.E., Fox, T.D., Mason, T.L. EMBO J. (1998) [Pubmed]
  3. A novel type of + 1 frameshift suppressor: a base substitution in the anticodon stem of a yeast mitochondrial serine-tRNA causes frameshift suppression. Hüttenhofer, A., Weiss-Brummer, B., Dirheimer, G., Martin, R.P. EMBO J. (1990) [Pubmed]
  4. Plasmids can stably transform yeast mitochondria lacking endogenous mtDNA. Fox, T.D., Sanford, J.C., McMullin, T.W. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  5. Peripheral mitochondrial inner membrane protein, Mss2p, required for export of the mitochondrially coded Cox2p C tail in Saccharomyces cerevisiae. Broadley, S.A., Demlow, C.M., Fox, T.D. Mol. Cell. Biol. (2001) [Pubmed]
  6. Pet111p, an inner membrane-bound translational activator that limits expression of the Saccharomyces cerevisiae mitochondrial gene COX2. Green-Willms, N.S., Butler, C.A., Dunstan, H.M., Fox, T.D. J. Biol. Chem. (2001) [Pubmed]
  7. T7 RNA polymerase-dependent expression of COXII in yeast mitochondria. Pinkham, J.L., Dudley, A.M., Mason, T.L. Mol. Cell. Biol. (1994) [Pubmed]
  8. In vivo analysis of mutated initiation codons in the mitochondrial COX2 gene of Saccharomyces cerevisiae fused to the reporter gene ARG8m reveals lack of downstream reinitiation. Bonnefoy, N., Fox, T.D. Mol. Gen. Genet. (2000) [Pubmed]
  9. Cox18p is required for export of the mitochondrially encoded Saccharomyces cerevisiae Cox2p C-tail and interacts with Pnt1p and Mss2p in the inner membrane. Saracco, S.A., Fox, T.D. Mol. Biol. Cell (2002) [Pubmed]
  10. Som1, a third component of the yeast mitochondrial inner membrane peptidase complex that contains Imp1 and Imp2. Jan, P.S., Esser, K., Pratje, E., Michaelis, G. Mol. Gen. Genet. (2000) [Pubmed]
  11. A mutation in cytochrome oxidase subunit 2 restores respiration of the mutant pet ts1402. Meyer, W., Bauer, M., Pratje, E. Curr. Genet. (1997) [Pubmed]
  12. Second-site, intragenic alterations in the gene encoding subunit II of cytochrome c oxidase from yeast can suppress two different missense mutations. Machingo, Q., Mazourek, M., Cameron, V. Curr. Genet. (2001) [Pubmed]
  13. Yeast complementation reveals a role for an Arabidopsis thaliana late embryogenesis abundant (LEA)-like protein in oxidative stress tolerance. Mowla, S.B., Cuypers, A., Driscoll, S.P., Kiddle, G., Thomson, J., Foyer, C.H., Theodoulou, F.L. Plant J. (2006) [Pubmed]
  14. Molecular characterization of Saccharomyces cerevisiae Sco2p reveals a high degree of redundancy with Sco1p. Lode, A., Paret, C., Rödel, G. Yeast (2002) [Pubmed]
  15. Mitochondrial copper metabolism in yeast: interaction between Sco1p and Cox2p. Lode, A., Kuschel, M., Paret, C., Rödel, G. FEBS Lett. (2000) [Pubmed]
  16. Alteration of a novel dispensable mitochondrial ribosomal small-subunit protein, Rsm28p, allows translation of defective COX2 mRNAs. Williams, E.H., Bsat, N., Bonnefoy, N., Butler, C.A., Fox, T.D. Eukaryotic Cell (2005) [Pubmed]
  17. Cloning and characterization of COX18, a Saccharomyces cerevisiae PET gene required for the assembly of cytochrome oxidase. Souza, R.L., Green-Willms, N.S., Fox, T.D., Tzagoloff, A., Nobrega, F.G. J. Biol. Chem. (2000) [Pubmed]
  18. Absence of the mitochondrial AAA protease Yme1p restores F0-ATPase subunit accumulation in an oxa1 deletion mutant of Saccharomyces cerevisiae. Lemaire, C., Hamel, P., Velours, J., Dujardin, G. J. Biol. Chem. (2000) [Pubmed]
  19. Assembly of the mitochondrial membrane system. Analysis of the nucleotide sequence and transcripts in the oxi1 region of yeast mitochondrial DNA. Coruzzi, G., Bonitz, S.G., Thalenfeld, B.E., Tzagoloff, A. J. Biol. Chem. (1981) [Pubmed]
 
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