{"gene":"COX19","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2002,"finding":"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.","method":"Complementation cloning of respiratory-deficient mutant, subcellular fractionation, genetic epistasis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct genetic complementation, subcellular fractionation, and functional characterization in yeast; foundational paper replicated by subsequent work","pmids":["12171940"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Recombinant protein expression, copper-binding assays, site-directed mutagenesis of cysteine residues, in vivo functional complementation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical reconstitution combined with mutagenesis and in vivo functional validation","pmids":["17237235"],"is_preprint":false},{"year":2014,"finding":"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.","method":"In vitro oxidative folding assays, NMR, mass spectrometry, chemical folding induction with trifluoroethanol, site-specific mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution of the folding pathway in vitro with mutagenesis and NMR structural validation in a single rigorous study","pmids":["24569988"],"is_preprint":false},{"year":2015,"finding":"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.","method":"SILAC-based quantitative proteomics (interaction screen), co-immunoprecipitation, mutagenesis of conserved YL dipeptides and Cox11 cysteine","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — quantitative proteomic interaction screen plus reciprocal co-IP and mutagenesis, multiple orthogonal methods in single rigorous study","pmids":["25926683"],"is_preprint":false},{"year":2018,"finding":"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.","method":"NMD mutant analysis, 3'-UTR functional reporter assays, growth assays on non-fermentable carbon source with excess copper","journal":"Current genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional 3'-UTR analysis in NMD mutants with copper-level variation, single lab, two complementary methods","pmids":["30317392"],"is_preprint":false},{"year":2023,"finding":"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.","method":"RNA-chromatin immunoprecipitation, COX activity assay, ATP assay, xenograft mouse model, western blot","journal":"The Journal of nutrition","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrates direct promoter binding, combined with functional assays and in vivo xenograft, single lab","pmids":["38141772"],"is_preprint":false}],"current_model":"COX19 encodes a small twin CX9C intermembrane space protein that is imported into mitochondria via Mia40-catalyzed oxidative folding, where it transiently binds Cu(I) through its conserved cysteine residues and interacts in a redox-regulated manner with the copper chaperone Cox11 to facilitate copper delivery to the CuB center of cytochrome c oxidase subunit 1, thereby acting as a post-translational assembly factor for the respiratory complex; its mRNA is additionally subject to NMD-mediated regulation linked to copper homeostasis, and in human cancer cells MACC1 drives its transcription to enhance mitochondrial copper import and oxidase activity."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2002,"claim":"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","pmids":["12171940"],"confidence":"High","gaps":["Molecular activity at the assembly step undefined","No biochemical substrate or partner identified"]},{"year":2007,"claim":"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","pmids":["17237235"],"confidence":"High","gaps":["Copper donor/acceptor partners not identified","Physiological relevance of dimerization unresolved"]},{"year":2014,"claim":"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","pmids":["24569988"],"confidence":"High","gaps":["Coupling of folding to copper loading not established","Kinetics of the uncatalyzed final oxidation step in vivo unclear"]},{"year":2015,"claim":"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","pmids":["25926683"],"confidence":"High","gaps":["Direction of copper transfer between Cox19 and Cox11 not directly demonstrated","Structure of the Cox19-Cox11 complex unknown"]},{"year":2018,"claim":"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","pmids":["30317392"],"confidence":"Medium","gaps":["Mechanism by which copper modulates NMD targeting not defined","Single-lab finding without orthogonal confirmation"]},{"year":2023,"claim":"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","pmids":["38141772"],"confidence":"Medium","gaps":["Whether COX19 is rate-limiting for oxidase activity in human cells unresolved","Single-lab finding; human Cox19 mechanism inferred from yeast"]},{"year":null,"claim":"The directionality and stoichiometry of copper transfer through the Cox19-Cox11 axis and a structural model of the metalation handoff remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of the Cox19-Cox11 complex or copper-loaded Cox19","Copper source feeding Cox19 in the IMS unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2]}],"complexes":[],"partners":["COX11","MIA40"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q49B96","full_name":"Cytochrome c oxidase assembly protein COX19","aliases":[],"length_aa":90,"mass_kda":10.4,"function":"Assembly factor for cytochrome c oxidase (respiratory chain complex IV, CIV) (PubMed:35750769). Acts as a COX11 chaperone that supports COX11 copper coordination (PubMed:35750769). Also stimulates SCO2-mediated metalation of COX2 (PubMed:35750769). Required for the transduction of an SCO1-dependent redox signal from the mitochondrion to ATP7A to regulate cellular copper homeostasis (PubMed:23345593). In the absence of COX11, capable of stimulating copper delivery to the copper B site of COX1 (PubMed:35750769)","subcellular_location":"Cytoplasm, cytosol; Mitochondrion intermembrane space; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q49B96/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COX19","classification":"Not Classified","n_dependent_lines":388,"n_total_lines":1208,"dependency_fraction":0.3211920529801324},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/COX19","total_profiled":1310},"omim":[{"mim_id":"613920","title":"CYTOCHROME C OXIDASE ASSEMBLY FACTOR 5; COA5","url":"https://www.omim.org/entry/613920"},{"mim_id":"610429","title":"CYTOCHROME c OXIDASE ASSEMBLY FACTOR COX19; COX19","url":"https://www.omim.org/entry/610429"},{"mim_id":"604272","title":"SCO CYTOCHROME c OXIDASE ASSEMBLY PROTEIN 2; SCO2","url":"https://www.omim.org/entry/604272"},{"mim_id":"603644","title":"SYNTHESIS OF CYTOCHROME c OXIDASE 1; SCO1","url":"https://www.omim.org/entry/603644"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/COX19"},"hgnc":{"alias_symbol":["MGC104475"],"prev_symbol":[]},"alphafold":{"accession":"Q49B96","domains":[{"cath_id":"-","chopping":"31-76","consensus_level":"high","plddt":92.8422,"start":31,"end":76}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q49B96","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q49B96-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q49B96-F1-predicted_aligned_error_v6.png","plddt_mean":80.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COX19","jax_strain_url":"https://www.jax.org/strain/search?query=COX19"},"sequence":{"accession":"Q49B96","fasta_url":"https://rest.uniprot.org/uniprotkb/Q49B96.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q49B96/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q49B96"}},"corpus_meta":[{"pmid":"12171940","id":"PMC_12171940","title":"Characterization of COX19, a widely distributed gene required for expression of mitochondrial cytochrome oxidase.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12171940","citation_count":85,"is_preprint":false},{"pmid":"25926683","id":"PMC_25926683","title":"Redox-regulated dynamic interplay between Cox19 and the copper-binding protein Cox11 in the intermembrane space of mitochondria facilitates biogenesis of cytochrome c oxidase.","date":"2015","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/25926683","citation_count":59,"is_preprint":false},{"pmid":"17237235","id":"PMC_17237235","title":"characterization of the cytochrome c oxidase assembly factor Cox19 of Saccharomyces cerevisiae.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17237235","citation_count":50,"is_preprint":false},{"pmid":"26309536","id":"PMC_26309536","title":"MicroRNA-21 regulates non-small cell lung cancer cell proliferation by affecting cell apoptosis via COX-19.","date":"2015","source":"International journal of clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26309536","citation_count":31,"is_preprint":false},{"pmid":"24569988","id":"PMC_24569988","title":"The mitochondrial intermembrane space oxireductase Mia40 funnels the oxidative folding pathway of the cytochrome c oxidase assembly protein Cox19.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24569988","citation_count":16,"is_preprint":false},{"pmid":"30317392","id":"PMC_30317392","title":"The nonsense-mediated mRNA decay (NMD) pathway differentially regulates COX17, COX19 and COX23 mRNAs.","date":"2018","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30317392","citation_count":11,"is_preprint":false},{"pmid":"15596615","id":"PMC_15596615","title":"Studies of COX16, COX19, and PET191 in human cytochrome-c oxidase deficiency.","date":"2004","source":"Archives of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/15596615","citation_count":8,"is_preprint":false},{"pmid":"38141772","id":"PMC_38141772","title":"COX19 Is a New Target of MACC1 and Promotes Colorectal Cancer Progression by Regulating Copper Transport in Mitochondria.","date":"2023","source":"The Journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/38141772","citation_count":7,"is_preprint":false},{"pmid":"37348640","id":"PMC_37348640","title":"Expression and copper binding studies of a Plasmodium falciparum protein with Cox19 copper binding motifs.","date":"2023","source":"Experimental parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/37348640","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6199,"output_tokens":1652,"usd":0.021688,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8496,"output_tokens":2272,"usd":0.04964,"stage2_stop_reason":"end_turn"},"total_usd":0.071328,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Complementation cloning of respiratory-deficient mutant, subcellular fractionation, genetic epistasis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct genetic complementation, subcellular fractionation, and functional characterization in yeast; foundational paper replicated by subsequent work\",\n      \"pmids\": [\"12171940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Recombinant protein expression, copper-binding assays, site-directed mutagenesis of cysteine residues, in vivo functional complementation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical reconstitution combined with mutagenesis and in vivo functional validation\",\n      \"pmids\": [\"17237235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro oxidative folding assays, NMR, mass spectrometry, chemical folding induction with trifluoroethanol, site-specific mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution of the folding pathway in vitro with mutagenesis and NMR structural validation in a single rigorous study\",\n      \"pmids\": [\"24569988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"SILAC-based quantitative proteomics (interaction screen), co-immunoprecipitation, mutagenesis of conserved YL dipeptides and Cox11 cysteine\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quantitative proteomic interaction screen plus reciprocal co-IP and mutagenesis, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"25926683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"NMD mutant analysis, 3'-UTR functional reporter assays, growth assays on non-fermentable carbon source with excess copper\",\n      \"journal\": \"Current genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional 3'-UTR analysis in NMD mutants with copper-level variation, single lab, two complementary methods\",\n      \"pmids\": [\"30317392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"RNA-chromatin immunoprecipitation, COX activity assay, ATP assay, xenograft mouse model, western blot\",\n      \"journal\": \"The Journal of nutrition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrates direct promoter binding, combined with functional assays and in vivo xenograft, single lab\",\n      \"pmids\": [\"38141772\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COX19 encodes a small twin CX9C intermembrane space protein that is imported into mitochondria via Mia40-catalyzed oxidative folding, where it transiently binds Cu(I) through its conserved cysteine residues and interacts in a redox-regulated manner with the copper chaperone Cox11 to facilitate copper delivery to the CuB center of cytochrome c oxidase subunit 1, thereby acting as a post-translational assembly factor for the respiratory complex; its mRNA is additionally subject to NMD-mediated regulation linked to copper homeostasis, and in human cancer cells MACC1 drives its transcription to enhance mitochondrial copper import and oxidase activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0]. 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 [#1]. 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 [#2]. 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 [#3]. COX19 expression is integrated with copper homeostasis: its mRNA is a direct NMD substrate modulated by environmental copper [#4], and in human colorectal cancer cells MACC1 transcriptionally activates COX19 to raise mitochondrial copper, oxidase activity, ATP production, and tumor growth [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"Complementation cloning of a respiratory-deficient yeast mutant with subcellular fractionation and genetic epistasis\",\n      \"pmids\": [\"12171940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular activity at the assembly step undefined\", \"No biochemical substrate or partner identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Recombinant protein copper-binding assays, cysteine mutagenesis, and in vivo functional complementation in yeast\",\n      \"pmids\": [\"17237235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Copper donor/acceptor partners not identified\", \"Physiological relevance of dimerization unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro oxidative folding assays with NMR, mass spectrometry, and site-specific mutants\",\n      \"pmids\": [\"24569988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coupling of folding to copper loading not established\", \"Kinetics of the uncatalyzed final oxidation step in vivo unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"SILAC quantitative proteomic interaction screen with reciprocal co-IP and mutagenesis of conserved YL dipeptides and a Cox11 cysteine\",\n      \"pmids\": [\"25926683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direction of copper transfer between Cox19 and Cox11 not directly demonstrated\", \"Structure of the Cox19-Cox11 complex unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed COX19 expression is regulated post-transcriptionally by NMD in a copper-responsive manner, integrating the assembly factor into cellular copper homeostasis.\",\n      \"evidence\": \"NMD mutant analysis and 3'-UTR reporter assays with copper-level variation in yeast\",\n      \"pmids\": [\"30317392\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which copper modulates NMD targeting not defined\", \"Single-lab finding without orthogonal confirmation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended COX19 biology to human disease by identifying MACC1-driven transcriptional activation that boosts mitochondrial copper, oxidase activity, and tumor growth.\",\n      \"evidence\": \"RNA-ChIP for promoter binding plus COX activity/ATP assays and a colorectal cancer xenograft model\",\n      \"pmids\": [\"38141772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether COX19 is rate-limiting for oxidase activity in human cells unresolved\", \"Single-lab finding; human Cox19 mechanism inferred from yeast\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The directionality and stoichiometry of copper transfer through the Cox19-Cox11 axis and a structural model of the metalation handoff remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the Cox19-Cox11 complex or copper-loaded Cox19\", \"Copper source feeding Cox19 in the IMS unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005758\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"COX11\", \"MIA40\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}