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Literature summary for 1.8.4.2 extracted from

  • Soma, S.; Morgada, M.N.; Naik, M.T.; Boulet, A.; Roesler, A.A.; Dziuba, N.; Ghosh, A.; Yu, Q.; Lindahl, P.A.; Ames, J.B.; Leary, S.C.; Vila, A.J.; Gohil, V.M.
    COA6 is structurally tuned to function as a thiol-disulfide oxidoreductase in copper delivery to mitochondrial cytochrome c oxidase (2019), Cell Rep., 29, 4114-4126.e5 .
    View publication on PubMedView publication on EuropePMC
Search for more literature for 1.8.4.2

Cloned(Commentary)

Cloned (Comment) Organism
recombiant expression of codon optimized His-tagged wild-type and mutant enzymes in Escherichia coli strain BL21(DE3) Saccharomyces cerevisiae
recombinant expression of GST-tagged wild-type and mutant enzymes in Escherichia coli strain BL21(DE3). Overexpression of the wild-type and mutant alleles of COA6 in control and COA6 patient fibroblasts Homo sapiens

Protein Variants

Protein Variants Comment Organism
additional information introduction of the patient mutations (W59C/E87X and W66R) into a human-yeast chimera (hyCOA6) that consists of the bulk of the human protein and the N-terminal 24 amino acid residues of yeast Coa6 to facilitate mitochondrial targeting. The respiratory growth of the knockout mutant coa6DELTA cells is restored by the chimeric mutant hyCOA6, but not by either of the tryptophan variants, suggesting that these missense mutations disrupt COA6 function or expression. The hyCOA6W26C mutant is expressed and localizes to mitochondria, while hyCOA6W33R and the truncated protein hyCOA6E54X are undetectable. Overexpression of the wild-type and mutant alleles of COA6 in control and COA6 patient fibroblasts shows that the W66R variant fails to rescue CcO activity. In contrast, expression of the W59C mutant leads to a partial recovery of CcO activity and COX2 levels Homo sapiens
W59C/E87X naturally occuring mutation in a human mitochondrial disease patient, mapping onto the COA6 structure. The truncation mutation (E87X) clearly disrupts the CHCH domain by removing a large portion of the protein from helix 2 onward. Mutation W59C is found within the first helix of COA6, where the side chain of the tryptophan faces the bulk solvent. The missense mutation disrupts COA6 function or expression. The patient with the W59C mutation exhibits a severe CcO deficiency in cardiac tissue Homo sapiens
W66R naturally occuring mutation in a human mitochondrial disease patient, mapping onto the COA6 structure. Mutation W66R is found within the first helix of COA6, where the side chain of the tryptophan faces the bulk solvent. The missense mutation disrupts COA6 function or expression Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
mitochondrial intermembrane space
-
 Saccharomyces cerevisiae 5758
-
mitochondrial intermembrane space
-
 Homo sapiens 5758
-

Metals/Ions

Metals/Ions Comment Organism Structure
Cu2+ human COA6 binds Cu with high affinity in vitro Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2 glutathione + COX2-disulfide Saccharomyces cerevisiae
-
 glutathione-disulfide + COX2-dithiol
-
 ?
2 glutathione + COX2-disulfide Homo sapiens
-
 glutathione-disulfide + COX2-dithiol
-
 ?
2 glutathione + COX2-disulfide Saccharomyces cerevisiae ATCC 204508
-
 glutathione-disulfide + COX2-dithiol
-
 ?
2 glutathione + protein-disulfide Saccharomyces cerevisiae
-
 glutathione-disulfide + protein-dithiol
-
 ?
2 glutathione + protein-disulfide Homo sapiens
-
 glutathione-disulfide + protein-dithiol
-
 ?
2 glutathione + protein-disulfide Saccharomyces cerevisiae ATCC 204508
-
 glutathione-disulfide + protein-dithiol
-
 ?
2 glutathione + SCO1-disulfide Saccharomyces cerevisiae
-
 glutathione-disulfide + SCO1-dithiol
-
 ?
2 glutathione + SCO1-disulfide Homo sapiens
-
 glutathione-disulfide + SCO1-dithiol
-
 ?
2 glutathione + SCO1-disulfide Saccharomyces cerevisiae ATCC 204508
-
 glutathione-disulfide + SCO1-dithiol
-
 ?
2 glutathione + SCO2-disulfide Saccharomyces cerevisiae
-
 glutathione-disulfide + SCO2-dithiol
-
 ?
additional information Saccharomyces cerevisiae COA6 interacts with COX2 and SCO proteins in vivo ?
-
-
additional information Homo sapiens COA6 interacts with COX2 and SCO proteins in vivo ?
-
-
additional information Saccharomyces cerevisiae ATCC 204508 COA6 interacts with COX2 and SCO proteins in vivo ?
-
-

Organism

Organism UniProt Comment Textmining
Homo sapiens Q5JTJ3
-
-
Saccharomyces cerevisiae Q3E846
-
-
Saccharomyces cerevisiae ATCC 204508 Q3E846
-
-

Purification (Commentary)

Purification (Comment) Organism
recombiant GST-tagged wild-type and mutant enzymes from Escherichia coli strain BL21(DE3) by glutathione affinity chromatography and gel filtration Homo sapiens
recombiant His-tagged wild-type and mutant enzymes from Escherichia coli strain BL21(DE3) by nickel affinity chromatography and gel filtration Saccharomyces cerevisiae

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2 glutathione + COX2-disulfide
-
 Saccharomyces cerevisiae glutathione-disulfide + COX2-dithiol
-
 ?
2 glutathione + COX2-disulfide
-
 Homo sapiens glutathione-disulfide + COX2-dithiol
-
 ?
2 glutathione + COX2-disulfide
-
 Saccharomyces cerevisiae ATCC 204508 glutathione-disulfide + COX2-dithiol
-
 ?
2 glutathione + protein-disulfide
-
 Saccharomyces cerevisiae glutathione-disulfide + protein-dithiol
-
 ?
2 glutathione + protein-disulfide
-
 Homo sapiens glutathione-disulfide + protein-dithiol
-
 ?
2 glutathione + protein-disulfide
-
 Saccharomyces cerevisiae ATCC 204508 glutathione-disulfide + protein-dithiol
-
 ?
2 glutathione + SCO1-disulfide
-
 Saccharomyces cerevisiae glutathione-disulfide + SCO1-dithiol
-
 ?
2 glutathione + SCO1-disulfide
-
 Homo sapiens glutathione-disulfide + SCO1-dithiol
-
 ?
2 glutathione + SCO1-disulfide
-
 Saccharomyces cerevisiae ATCC 204508 glutathione-disulfide + SCO1-dithiol
-
 ?
2 glutathione + SCO2-disulfide
-
 Saccharomyces cerevisiae glutathione-disulfide + SCO2-dithiol
-
 ?
additional information COA6 interacts with COX2 and SCO proteins in vivo Saccharomyces cerevisiae ?
-
-
additional information COA6 interacts with COX2 and SCO proteins in vivo Homo sapiens ?
-
-
additional information at least in vitro SCO1 is the dominant interacting partner of COA6 compared to SCO2. H3 and C-terminal residues of COA6 are critical for its interaction with SCO1 Homo sapiens ?
-
-
additional information yeast Coa6 interacts with both Sco1 and Sco2 Saccharomyces cerevisiae ?
-
-
additional information COA6 interacts with COX2 and SCO proteins in vivo Saccharomyces cerevisiae ATCC 204508 ?
-
-
additional information yeast Coa6 interacts with both Sco1 and Sco2 Saccharomyces cerevisiae ATCC 204508 ?
-
-

Subunits

Subunits Comment Organism
dimer dimerization of COA6 is unaffected by its concentration. The residues in helix 3 of COA6 are likely involved in dimerization. Dimerization is not due to inter-disulfide bonding between cysteine residues of each COA6 monomer. COA6 structure analysis, overview Saccharomyces cerevisiae
dimer dimerization of COA6 is unaffected by its concentration. The residues in helix 3 of COA6 are likely involved in dimerization. Dimerization is not due to inter-disulfide bonding between cysteine residues of each COA6 monomer. COA6 structure analysis, overview Homo sapiens

Synonyms

Synonyms Comment Organism
C1orf31
-
 Homo sapiens
COA6
-
 Saccharomyces cerevisiae
COA6
-
 Homo sapiens
YMR244C-A
-
 Saccharomyces cerevisiae

General Information

General Information Comment Organism
malfunction the truncation mutation (E87X) clearly disrupts the CHCH domain by removing a large portion of the protein from helix 2 onward. The other two mutations, W59C and W66R, are found within the first helix of COA6, where the side chains of each tryptophan face the bulk solvent, suggesting that these residues may facilitate interactions with their client proteins. Overexpression of the wild-type and mutant alleles of COA6 in control and COA6 patient fibroblasts shows that the W66R variant fails to rescue CcO activity. In contrast, expression of the W59C mutant leads to a partial recovery of CcO activity and COX2 levels. It seems that in most cell types residual levels of the partially functional W59C allele are not sufficient to support CcO assembly and mitochondrial respiration because coa6DELTA cells expressing the W59C variant do not exhibit respiratory growth. The human patient with the W59C mutation exhibits a severe CcO deficiency in cardiac tissue Homo sapiens
additional information the solution structure of COA6 reveals a coiled-coil-helix-coiled-coil-helix domain typical of redox-active proteins found in the mitochondrial inter-membrane space. COA6 structure analysis by NMR spectroscopy, overview Saccharomyces cerevisiae
additional information the solution structure of COA6 reveals a coiled-coil-helix-coiled-coil-helix domain typical of redox-active proteins found in the mitochondrial inter-membrane space. COA6 structure analysis by NMR spectroscopy, overview. The conserved tryptophans W59 and W66 are critical for COA6 stability and possibly for their interactions with client proteins Homo sapiens
physiological function in eukaryotes, cellular respiration is driven by mitochondrial cytochrome c oxidase (CcO), an enzyme complex that requires copper cofactors for its catalytic activity. Insertion of copper into its catalytically active subunits, including COX2, is a complex process that requires metallochaperones and redox proteins including SCO1, SCO2, and COA6. COA6 is structurally tuned to function as a thiol-disulfide oxidoreductase in copper delivery to mitochondrial cytochrome c oxidase. COA6 can reduce the copper-coordinating disulfides of its client proteins, SCO1 and COX2, allowing for copper binding. Determination of the interaction surfaces and reduction potentials of COA6 and its client proteins provides a mechanism of how metallochaperone and disulfide reductase activities are coordinated to deliver copper to CcO, overview. COA6 acts as a disulfide reductase of SCO and COX2 proteins Saccharomyces cerevisiae
physiological function in eukaryotes, cellular respiration is driven by mitochondrial cytochrome c oxidase (CcO), an enzyme complex that requires copper cofactors for its catalytic activity. Insertion of copper into its catalytically active subunits, including COX2, is a complex process that requires metallochaperones and redox proteins including SCO1, SCO2, and COA6. COA6 is structurally tuned to function as a thiol-disulfide oxidoreductase in copper delivery to mitochondrial cytochrome c oxidase. COA6 can reduce the copper-coordinating disulfides of its client proteins, SCO1 and COX2, allowing for copper binding. Determination of the interaction surfaces and reduction potentials of COA6 and its client proteins provides a mechanism of how metallochaperone and disulfide reductase activities are coordinated to deliver copper to CcO, overview. COA6 function can be bypassed in a reducing environment. Coa6 has a redox as opposed to a metallochaperone function in Cu delivery to Cox2. COA6 acts as a disulfide reductase of SCO and COX2 proteins. COA6 can reduce the disulfides of SCO proteins, generating free sulfhydryl groups. COA6 can also reduce the cysteines of COX2 Homo sapiens