Affinage

COX19

Cytochrome c oxidase assembly protein COX19 · UniProt Q49B96

Length
90 aa
Mass
10.4 kDa
Annotated
2026-06-09
9 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

COX19 encodes a small, nuclear-encoded twin CX9C protein that functions as a post-translational assembly factor for cytochrome c oxidase, partitioning between the cytoplasm and the mitochondrial intermembrane space (PMID:12171940). It folds into a helical hairpin and transiently coordinates one Cu(I) per monomer through conserved cysteines that are required both for copper binding in vitro and for oxidase assembly in vivo, consistent with a role in mitochondrial copper handling (PMID:17237235). Import and maturation depend on the IMS oxidoreductase Mia40, which recognizes a specific cysteine in the second CX9C motif and catalyzes inner disulfide formation to drive native oxidative folding (PMID:24569988). Within the IMS, Cox19 binds the copper transfer protein Cox11 in a redox-regulated manner through a hydrophobic surface formed by two conserved tyrosine-leucine dipeptides; this interaction, stimulated by oxidative modification of a Cox11 cysteine, links Cox19 to metalation of the CuB center of cytochrome c oxidase subunit 1 and is required for stable mitochondrial accumulation of Cox19 (PMID:25926683). COX19 expression is integrated with copper homeostasis: its mRNA is a direct NMD substrate modulated by environmental copper (PMID:30317392), and in human colorectal cancer cells MACC1 transcriptionally activates COX19 to raise mitochondrial copper, oxidase activity, ATP production, and tumor growth (PMID:38141772).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2002 High

    Established that Cox19 is a dedicated, post-translationally acting cytochrome oxidase assembly factor rather than a structural subunit, narrowing its role to a maturation step.

    Evidence Complementation cloning of a respiratory-deficient yeast mutant with subcellular fractionation and genetic epistasis

    PMID:12171940

    Open questions at the time
    • Molecular activity at the assembly step undefined
    • No biochemical substrate or partner identified
  2. 2007 High

    Answered what Cox19 does biochemically by showing it adopts a twin CX9C fold and transiently binds Cu(I) via cysteines essential for function, linking it directly to copper handling in oxidase assembly.

    Evidence Recombinant protein copper-binding assays, cysteine mutagenesis, and in vivo functional complementation in yeast

    PMID:17237235

    Open questions at the time
    • Copper donor/acceptor partners not identified
    • Physiological relevance of dimerization unresolved
  3. 2014 High

    Resolved how Cox19 is imported and folded, showing Mia40 catalyzes inner disulfide formation on a specific cysteine to funnel the folding landscape and trap the protein in the IMS.

    Evidence In vitro oxidative folding assays with NMR, mass spectrometry, and site-specific mutants

    PMID:24569988

    Open questions at the time
    • Coupling of folding to copper loading not established
    • Kinetics of the uncatalyzed final oxidation step in vivo unclear
  4. 2015 High

    Connected Cox19 to the downstream metalation machinery by identifying a redox-regulated interaction with Cox11, defining how copper handling links to CuB center formation in Cox1.

    Evidence SILAC quantitative proteomic interaction screen with reciprocal co-IP and mutagenesis of conserved YL dipeptides and a Cox11 cysteine

    PMID:25926683

    Open questions at the time
    • Direction of copper transfer between Cox19 and Cox11 not directly demonstrated
    • Structure of the Cox19-Cox11 complex unknown
  5. 2018 Medium

    Showed COX19 expression is regulated post-transcriptionally by NMD in a copper-responsive manner, integrating the assembly factor into cellular copper homeostasis.

    Evidence NMD mutant analysis and 3'-UTR reporter assays with copper-level variation in yeast

    PMID:30317392

    Open questions at the time
    • Mechanism by which copper modulates NMD targeting not defined
    • Single-lab finding without orthogonal confirmation
  6. 2023 Medium

    Extended COX19 biology to human disease by identifying MACC1-driven transcriptional activation that boosts mitochondrial copper, oxidase activity, and tumor growth.

    Evidence RNA-ChIP for promoter binding plus COX activity/ATP assays and a colorectal cancer xenograft model

    PMID:38141772

    Open questions at the time
    • Whether COX19 is rate-limiting for oxidase activity in human cells unresolved
    • Single-lab finding; human Cox19 mechanism inferred from yeast

Open questions

Synthesis pass · forward-looking unresolved questions
  • The directionality and stoichiometry of copper transfer through the Cox19-Cox11 axis and a structural model of the metalation handoff remain unresolved.
  • No structure of the Cox19-Cox11 complex or copper-loaded Cox19
  • Copper source feeding Cox19 in the IMS unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140104 molecular carrier activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-392499 Metabolism of proteins 1
Partners
COX11MIA40

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Cox19p is a nuclear-encoded ~11 kDa protein required for cytochrome oxidase assembly. It localizes to both the cytoplasm and the mitochondrial intermembrane space as a soluble protein. Because cox19 null mutants can synthesize mitochondrial and nuclear gene products of cytochrome oxidase, Cox19p functions post-translationally during enzyme assembly. Its four cysteines align with a subset of cysteines in the copper chaperone Cox17p. Complementation cloning of respiratory-deficient mutant, subcellular fractionation, genetic epistasis The Journal of biological chemistry High 12171940
2007 Cox19 adopts a twin CX9C helical hairpin structure and can coordinate Cu(I): recombinant Cox19 binds 1 mol equivalent of Cu(I) per monomer and exists as a dimer. Cysteinyl residues required for Cu(I) binding are also required for in vivo function in cytochrome c oxidase assembly. Cox19 isolated from the mitochondrial IMS contains variable copper, suggesting Cu(I) binding is transient. Recombinant protein expression, copper-binding assays, site-directed mutagenesis of cysteine residues, in vivo functional complementation The Journal of biological chemistry High 17237235
2014 Mia40, the mitochondrial IMS oxidoreductase, drives oxidative folding and import of Cox19. Mia40 specifically recognizes the third Cys in the second CX9C motif of Cox19 and catalyzes formation of the inner disulfide bond, generating a native-like intermediate that subsequently oxidizes slowly in an uncatalyzed step to produce native Cox19. This funnels the folding landscape and prevents accumulation of kinetic traps. In vitro oxidative folding assays, NMR, mass spectrometry, chemical folding induction with trifluoroethanol, site-specific mutants The Journal of biological chemistry High 24569988
2015 Cox19 interacts dynamically and in a redox-regulated manner with Cox11, a copper transfer protein required for metalation of the CuB center of cytochrome c oxidase subunit 1. The interaction depends on a hydrophobic surface formed by two conserved tyrosine-leucine dipeptides on Cox19; these residues are essential for Cox19 function and for specific binding to a cysteine-containing sequence in Cox11. Oxidative modification of this Cox11 cysteine stimulates Cox19 binding. The interaction with Cox11 is also critical for stable accumulation of Cox19 in mitochondria. SILAC-based quantitative proteomics (interaction screen), co-immunoprecipitation, mutagenesis of conserved YL dipeptides and Cox11 cysteine Molecular biology of the cell High 25926683
2018 The COX19 mRNA is a direct substrate of the nonsense-mediated mRNA decay (NMD) pathway in yeast; a long 3'-UTR contributes to this direct regulation. NMD-mediated regulation of COX19 mRNA is modulated by environmental copper levels. NMD mutant analysis, 3'-UTR functional reporter assays, growth assays on non-fermentable carbon source with excess copper Current genetics Medium 30317392
2023 MACC1 transcriptionally activates COX19 by binding to its promoter. Overexpression of COX19 increases mitochondrial copper content, enhances cytochrome c oxidase activity and ATP production, and promotes colorectal cancer tumor growth in a xenograft mouse model. RNA-chromatin immunoprecipitation, COX activity assay, ATP assay, xenograft mouse model, western blot The Journal of nutrition Medium 38141772

Source papers

Stage 0 corpus · 9 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Characterization of COX19, a widely distributed gene required for expression of mitochondrial cytochrome oxidase. The Journal of biological chemistry 85 12171940
2015 Redox-regulated dynamic interplay between Cox19 and the copper-binding protein Cox11 in the intermembrane space of mitochondria facilitates biogenesis of cytochrome c oxidase. Molecular biology of the cell 59 25926683
2007 characterization of the cytochrome c oxidase assembly factor Cox19 of Saccharomyces cerevisiae. The Journal of biological chemistry 50 17237235
2015 MicroRNA-21 regulates non-small cell lung cancer cell proliferation by affecting cell apoptosis via COX-19. International journal of clinical and experimental medicine 31 26309536
2014 The mitochondrial intermembrane space oxireductase Mia40 funnels the oxidative folding pathway of the cytochrome c oxidase assembly protein Cox19. The Journal of biological chemistry 16 24569988
2018 The nonsense-mediated mRNA decay (NMD) pathway differentially regulates COX17, COX19 and COX23 mRNAs. Current genetics 11 30317392
2004 Studies of COX16, COX19, and PET191 in human cytochrome-c oxidase deficiency. Archives of neurology 8 15596615
2023 COX19 Is a New Target of MACC1 and Promotes Colorectal Cancer Progression by Regulating Copper Transport in Mitochondria. The Journal of nutrition 7 38141772
2023 Expression and copper binding studies of a Plasmodium falciparum protein with Cox19 copper binding motifs. Experimental parasitology 2 37348640

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