{"gene":"SCO1","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":1988,"finding":"Yeast SCO1 is required for a post-transcriptional step in the accumulation of mitochondrially synthesized cytochrome c oxidase subunit II (CoxII); Northern blot showed normal transcription/mRNA maturation of OXI1, but CoxII protein was strongly reduced in sco1-1 mutant, indicating SCO1 acts post-transcriptionally.","method":"Yeast genetic analysis, mitochondrial translation product analysis, Northern blot hybridization","journal":"Molecular & general genetics : MGG","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with specific molecular phenotype, multiple analytical methods, single lab","pmids":["2835635"],"is_preprint":false},{"year":1989,"finding":"Yeast SCO1 encodes a 33 kDa protein that is imported into mitochondria and processed to a 30 kDa form tightly associated with the mitochondrial membrane, as shown by in vitro transcription/translation and mitochondrial import assays.","method":"In vitro transcription/translation, mitochondrial import assay, protease protection","journal":"Molecular & general genetics : MGG","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical import and fractionation experiments, single lab, two orthogonal methods","pmids":["2543907"],"is_preprint":false},{"year":1990,"finding":"SCO1 protein is required for a post-translational step: SCO1-deleted yeast translates CoxI and CoxII normally but the newly synthesized subunits are preferentially degraded, indicating SCO1 protects them from proteolysis during assembly.","method":"Yeast genetics, pulse-chase labeling of mitochondrial translation products","journal":"Current genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulse-chase establishes post-translational mechanism, single lab","pmids":["2173976"],"is_preprint":false},{"year":1991,"finding":"Yeast SCO1 protein localizes to the inner mitochondrial membrane as an integral membrane protein; membrane localization is mediated by a 17-amino-acid hydrophobic N-terminal segment, and removal of this segment abolishes both membrane binding and biological function.","method":"Subcellular fractionation, alkaline extraction, isopycnic sucrose gradient centrifugation, digitonin treatment, immunoblot with anti-SCO1 antibodies","journal":"Molecular & general genetics : MGG","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical fractionation methods, functional consequence of domain deletion demonstrated","pmids":["1944230"],"is_preprint":false},{"year":1996,"finding":"SCO1 and SCO2 act as high-copy suppressors of a COX17 copper-recruitment defect in yeast; SCO1 overexpression compensates for the absence of Cox17p, placing SCO1 downstream of COX17 in the mitochondrial copper delivery pathway to cytochrome c oxidase. SCO2 cannot suppress a sco1 null mutant, indicating non-identical functions.","method":"Yeast multicopy suppressor screen, genetic epistasis, null mutant complementation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple alleles and null mutants, clearly positions SCO1 in copper delivery pathway downstream of COX17","pmids":["8702795"],"is_preprint":false},{"year":1998,"finding":"Human SCO1 is the ortholog of yeast SCO1; the human protein contains conserved functional domains and is imported into mitochondria as shown by in vitro import and protease-protection assays.","method":"Sequence alignment, in vitro mitochondrial import assay, protease-protection assay","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical import assay with protease protection, single lab","pmids":["9878253"],"is_preprint":false},{"year":1999,"finding":"Both human SCO1 homologs (chromosomes 17 and 22) localize to mitochondria in HeLa cells when expressed as EGFP fusions; a chimera of the N-terminal half of yeast Sco1p and the C-terminal half of human chromosome-17 SCO1 complements the yeast sco1 deletion, but neither full-length human protein alone does.","method":"EGFP fusion live-cell imaging, yeast complementation assay with chimeric proteins","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by fluorescence imaging, complementation functional assay, single lab","pmids":["10218584"],"is_preprint":false},{"year":2000,"finding":"Pathogenic mutations in human SCO1 (2-bp frameshift and P174L missense in the conserved CxxxC copper-binding domain) cause isolated COX deficiency; the P174L mutation affects a conserved proline adjacent to the CxxxC copper-binding domain, likely disrupting its tertiary structure.","method":"Mutation screening, compound heterozygosity analysis, sequence conservation analysis","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — human genetics with structural inference, multiple mutations identified, replicated across patients","pmids":["11013136"],"is_preprint":false},{"year":2001,"finding":"Purified C-terminal domain of yeast Sco1 binds one Cu(I) per monomer via three ligands—two conserved cysteines in the CXXXC motif and a conserved histidine—as shown by X-ray absorption spectroscopy. Mutation of any one of these residues abolishes Sco1 function in yeast.","method":"Protein purification, X-ray absorption spectroscopy (XAS/EXAFS), site-directed mutagenesis, yeast functional assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical characterization with XAS, mutagenesis validated in vivo, multiple orthogonal methods","pmids":["11546815"],"is_preprint":false},{"year":2003,"finding":"Solution structure of Sco1 from Bacillus subtilis (NMR) reveals a thioredoxin-like fold with the copper-binding CXXXCP motif positioned analogously to the catalytic residues in thioredoxins; in vitro binding shows Cu(I) coordinated through CXXXCP and His135, and Cu(II) binding also occurs but appears adventitious.","method":"NMR structure determination, in vitro copper binding","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with in vitro copper binding characterization, bacterial ortholog structurally consistent with mammalian SCO1","pmids":["14604533"],"is_preprint":false},{"year":2003,"finding":"In SCO1-deficient patient fibroblasts, a COX subassembly containing MTCO1, COX4, and COX5A accumulates, indicating that SCO1 function is required for the subsequent association of MTCO2 with this subassembly (i.e., Cu(A) center formation in MTCO2 precedes MTCO2 incorporation into the assembly line).","method":"Blue native gel electrophoresis, immunoblot of COX subassemblies from patient fibroblasts","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — native gel with pathway inference in loss-of-function patient cells, single lab","pmids":["14607829"],"is_preprint":false},{"year":2004,"finding":"Cox17 directly and specifically transfers Cu(I) to both Sco1 and Cox11 in vitro using purified proteins; a C57Y mutant of Cox17 fails to transfer copper to Sco1 but retains ability to transfer to Cox11, demonstrating distinct transfer mechanisms. Metallation of cytoplasmic Sco1 in yeast is strictly dependent on co-expression of Cox17.","method":"In vitro copper transfer assay with purified proteins, yeast cytoplasmic expression system, Cox17 mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro copper transfer, mutagenesis, and in vivo yeast corroboration; multiple orthogonal methods","pmids":["15199057"],"is_preprint":false},{"year":2004,"finding":"Human SCO1 and SCO2 have non-overlapping cooperative functions: COX17 overexpression rescues COX deficiency in SCO2 but not SCO1 patient cells; overexpression of either SCO protein in the reciprocal patient background produces a dominant-negative phenotype suggesting physical interaction. SCO1 and SCO2 function as homodimers by size-exclusion chromatography. The dominant-negative effect in SCO2 background maps to the N-terminal domain of SCO1.","method":"Patient cell lines, overexpression rescue/dominant-negative assays, chimeric protein complementation, size-exclusion chromatography","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional approaches in patient cells, epistasis defined, dominant-negative domain mapping, single lab with comprehensive analysis","pmids":["15229189"],"is_preprint":false},{"year":2005,"finding":"Human Sco1 and Sco2 each bind Cu(I) (trigonal coordination) and Cu(II) (type II-like, higher coordination); Cu(I) binding requires two conserved cysteines and a histidine. Asp238 in human Sco1 is required for Cu(II) binding and normal in vivo function. Metallation of human Sco1 in yeast cytoplasm depends on co-expression of human Cox17, but Sco2 metallation does not.","method":"Protein expression in bacteria and yeast, X-ray absorption spectroscopy, site-directed mutagenesis, yeast functional assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple spectroscopic and mutagenesis methods, in vivo functional validation, two copper-binding modes characterized","pmids":["16091356"],"is_preprint":false},{"year":2005,"finding":"Crystal structure of human SCO1 (apo form, 2.8 Å) reveals a thioredoxin/peroxiredoxin-like fold with putative copper-binding ligands at positions equivalent to catalytic residues in Trx/Prx; SCO1 does not possess disulfide isomerization or peroxidase activity, but both human SCO1 and yeast sco1 null show extreme sensitivity to H2O2.","method":"X-ray crystallography, enzymatic activity assays (disulfide isomerization, peroxidase), H2O2 sensitivity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional activity assays in both human and yeast, multiple methods","pmids":["15659396"],"is_preprint":false},{"year":2006,"finding":"Solution structures of apo, Cu(I), and Ni(II) forms of human Sco1 (NMR) reveal that metal binding shifts the protein from an open, conformationally mobile state to a closed, rigid conformation. Cu(I) is coordinated by two Cys of the CPXXCP motif and a His residue. The Ni(II)-bound structure suggests the protein may also retain thioredoxin-like function in oxidized form.","method":"NMR structure determination, electrospray ionization mass spectrometry, X-ray crystallography of Ni(II) form","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple structures (apo, Cu(I), Ni(II)) by NMR and crystallography, conformational change characterized by ESI-MS","pmids":["16735468"],"is_preprint":false},{"year":2006,"finding":"Crystal structures of yeast apo-Sco1 (1.8 Å) and Cu-Sco1 (2.3 Å) show a thioredoxin-like fold; the conserved His239 is on a flexible 'Sco loop' proximal to both cysteine pairs; an unexpected copper-binding site involving non-conserved Cys181/Cys216 is observed in the soaked crystal. Electrostatic surface analysis suggests interaction sites with Cox17 and COX2.","method":"X-ray crystallography, copper soaking experiments","journal":"Journal of biological inorganic chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structures of both apo and copper-loaded forms, ortholog consistent with mammalian gene function","pmids":["16570183"],"is_preprint":false},{"year":2006,"finding":"The P174L pathogenic mutation of human Sco1 reduces Cu(I) binding affinity ~10,000-fold (KD ~10^-13 vs ~10^-17 M for wild-type), and impairs the transient Cox17/Cu(I)/Sco1 complex formation and copper transfer from Cu(I)Cox17 to Sco1, without abolishing copper binding entirely.","method":"NMR solution structure of mutant, Cu(I) affinity measurements, in vitro copper transfer assays, Cox17 interaction studies","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — structure, affinity measurement, and transfer assay combined in one study with quantitative KD values","pmids":["17182746"],"is_preprint":false},{"year":2006,"finding":"The P174L mutation in human Sco1 retains normal Cu(I) and Cu(II) binding when expressed in bacteria, but Cox17-mediated copper transfer to Sco1 is severely compromised both in vitro and in a yeast cytoplasmic assay. Pulse-chase labeling in SCO1 patient fibroblasts shows normal CoxII translation rate but rapid and specific turnover of newly synthesized CoxII.","method":"Protein expression and metal binding analysis, in vitro copper transfer assay, yeast cytoplasmic assay, pulse-chase labeling in patient fibroblasts","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted transfer assay, yeast assay, and pulse-chase in patient cells; comprehensive multi-method analysis","pmids":["16520371"],"is_preprint":false},{"year":2007,"finding":"Human SCO1 and SCO2 have additional roles in cellular copper homeostasis beyond COX assembly; mutations in either SCO result in tissue- and allele-specific cellular copper deficiency that can be dissociated from COX assembly defects. The copper deficiency reflects increased copper efflux, not decreased uptake, and is suppressed by SCO2 overexpression but not SCO1 overexpression.","method":"Patient cell lines, shRNA knockdown, copper efflux/uptake measurements, SCO overexpression rescue","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple patient backgrounds, shRNA controls, dissection of uptake vs. efflux, rescue experiments; comprehensive mechanistic dissection","pmids":["17189203"],"is_preprint":false},{"year":2008,"finding":"Cu(I)HCox17 (partially oxidized, 2S-S form) simultaneously transfers Cu(I) and two electrons to oxidized HSco1 (disulfide form), yielding Cu(I)HSco1 and fully oxidized apoHCox17; the reaction is thermodynamically driven by copper transfer. This coupled copper-electron transfer does not occur with HSco2 due to absence of a specific metal-bridged protein-protein complex.","method":"In vitro reconstitution with purified proteins, redox chemistry, NMR, thermodynamic analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with defined redox states, thermodynamic measurements, mechanistic distinction between Sco1 and Sco2","pmids":["18458339"],"is_preprint":false},{"year":2009,"finding":"SCO2 acts upstream of SCO1 in COX assembly: pulse-labeling shows COX II synthesis is reduced in SCO2 but not SCO1 patient cells; RNAi of mutant SCO2 abolishes COX II labeling. SCO2 acts as a thiol-disulfide oxidoreductase to oxidize the copper-coordinating cysteines in SCO1 during COX II maturation; the ratio of oxidized to reduced cysteines in SCO1 is perturbed in both SCO patient backgrounds and is corrected by SCO2 overexpression or knockdown.","method":"Mitochondrial translation pulse-labeling, RNAi knockdown, cysteine redox state analysis in patient fibroblasts, overexpression rescue","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — pulse-labeling defines upstream/downstream order, RNAi confirms, redox state of SCO1 cysteines directly measured; multiple orthogonal methods","pmids":["19336478"],"is_preprint":false},{"year":2009,"finding":"A fraction of Sco1 physically associates with the assembled COX complex in human muscle mitochondria as shown by blue native immunoblot and co-immunoprecipitation. The G132S mutation in SCO1 causes the protein to migrate exclusively as a monomer rather than a higher-order form, indicating the mutation disrupts oligomerization.","method":"Blue native gel electrophoresis, co-immunoprecipitation from human muscle mitochondria","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal methods (BN-PAGE + Co-IP) in patient and control tissue, single lab","pmids":["19295170"],"is_preprint":false},{"year":2011,"finding":"Despite global copper deficiency at the whole-cell level in SCO1 and SCO2 patient fibroblasts, total and exchangeable mitochondrial Cu(+) pools are largely maintained at normal levels, demonstrating that cells prioritize mitochondrial copper homeostasis even when SCO metallochaperones are dysfunctional.","method":"Fluorescent mitochondria-targeted copper sensor (Mito-CS1) live imaging, biochemical copper measurements in patient fibroblasts","journal":"Journal of the American Chemical Society","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — targeted fluorescent sensor with biochemical validation, patient fibroblast model, single lab","pmids":["21563821"],"is_preprint":false},{"year":2014,"finding":"COX20 interacts with newly synthesized COX2, and SCO1 and SCO2 act on COX20-bound COX2; COX20 acts as a chaperone stabilizing newly synthesized COX2 and presenting it to the SCO1/SCO2 metallochaperone module for Cu(A) site maturation prior to COX2 incorporation into early COX subassemblies.","method":"siRNA knockdown, TALEN knockout, immunoprecipitation of COX20-FLAG with newly synthesized COX2, subassembly analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP defines order of assembly, knockout cell lines, multiple loss-of-function approaches, pathway position established","pmids":["24403053"],"is_preprint":false},{"year":2015,"finding":"SCO1 is required to maintain CTR1 (the high-affinity copper importer) protein at steady-state levels; in Sco1-/- mouse embryonic fibroblasts, CTR1 is rapidly degraded and its levels are restored by proteasome inhibition, establishing a post-translational mitochondrial-to-plasma-membrane signaling axis through SCO1 that regulates cellular copper import.","method":"Liver-specific Sco1 knockout mice, immunoblot, proteasome inhibitor treatment in MEFs","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout mouse model, proteasome inhibitor rescue, mechanistic pathway established in vivo and in cells","pmids":["25683716"],"is_preprint":false},{"year":2017,"finding":"In the heart, SCO1 maintains CTR1 at the plasma membrane; cardiac-specific and striated-muscle-specific Sco1 deletion causes dilated cardiomyopathy with combined COX and copper deficiency, and CTR1 is mislocalised to the cytosol rather than degraded (unlike in liver), demonstrating tissue-specific consequences of SCO1 loss on CTR1 regulation.","method":"Heart- and striated-muscle-specific Sco1 knockout and knockin (G115S) mice, immunofluorescence for CTR1 localization, COX activity assays, copper measurements","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple tissue-specific mouse models including knockin, direct CTR1 localization imaging, functional COX and copper measurements","pmids":["28973536"],"is_preprint":false},{"year":2017,"finding":"SCO1 overexpression in adipocytes leads to intracellular copper deficiency, and this copper loss causes insulin resistance by increasing PTEN protein levels; addition of exogenous copper abolishes the insulin resistance caused by SCO1 overexpression, establishing SCO1 as a regulator of insulin sensitivity via copper levels in white adipose tissue.","method":"Overexpression in adipocytes, copper supplementation rescue, PTEN protein measurement, insulin sensitivity assays","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single overexpression approach, mechanistic connection to PTEN is indirect","pmids":["28647369"],"is_preprint":false},{"year":2022,"finding":"Copper-loaded SCO1 directly interacts with LKB1 and tethers LKB1 to AMPK, thereby activating AMPK and promoting mitochondrial biogenesis and fatty acid oxidation; SCO1 constitutively interacts with LKB1 even without copper, but copper loading is required for AMPK tethering and activation.","method":"Co-immunoprecipitation, SCO1 knockout and overexpression in mice and cells, AMPK activity assays, copper restoration experiments","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP defines SCO1-LKB1-AMPK complex, in vivo mouse model, copper-dependence established, single lab","pmids":["36261001"],"is_preprint":false},{"year":2025,"finding":"In an isogenic murine background, the heart is the most susceptible organ to SCO1 loss-of-function; Sco1G115S and Sco1P157L knockin hearts develop dilated cardiomyopathy with combined COX and copper deficiency including mitochondrial copper pool depletion, while brain-specific Sco1 knockout causes severe COX deficiency without altered copper content, demonstrating tissue-specific mechanisms of SCO1 function.","method":"Brain-specific Sco1 knockout mice, whole-body SCO1 knockin mice (G115S, P157L, M277V), COX activity assays, copper content measurements (including mitochondrial copper pool)","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple knockin alleles and tissue-specific knockouts in isogenic background, comprehensive phenotyping dissecting COX vs. copper functions by tissue","pmids":["40679281"],"is_preprint":false}],"current_model":"SCO1 is a mitochondrial inner membrane metallochaperone that, after receiving Cu(I) from Cox17 (via a coupled copper-electron transfer reaction), delivers copper to the Cu(A) site of cytochrome c oxidase subunit COX2 in cooperation with SCO2 (which acts upstream as a thiol-disulfide oxidoreductase to prepare SCO1's copper-coordinating cysteines); SCO1 also forms part of a COX20-SCO1-SCO2 maturation module for newly synthesized COX2, physically associates with assembled COX complex, and additionally signals from mitochondria to the plasma membrane to regulate CTR1-dependent cellular copper import and, through a copper-loaded SCO1-LKB1-AMPK complex, modulates cellular energy metabolism."},"narrative":{"mechanistic_narrative":"SCO1 is a copper-binding inner mitochondrial membrane metallochaperone that delivers copper to the Cu(A) site of cytochrome c oxidase subunit COX2, a function conserved from yeast to humans [PMID:8702795, PMID:9878253, PMID:11546815]. It is anchored as an integral inner-membrane protein via an N-terminal hydrophobic segment required for both membrane binding and function [PMID:1944230], and acts post-transcriptionally and post-translationally to protect and mature newly synthesized COX2, whose Cu(A) center must form before COX2 incorporates into the assembly line [PMID:2835635, PMID:2173976, PMID:14607829]. SCO1 adopts a thioredoxin-like fold and coordinates one Cu(I) per monomer through two cysteines of a CXXXC(P) motif and a conserved histidine, transitioning from an open to a closed conformation upon metal binding [PMID:11546815, PMID:14604533, PMID:16735468, PMID:16570183]. It receives copper from Cox17 through a coupled copper-electron transfer reaction in which partially oxidized Cu(I)Cox17 simultaneously transfers Cu(I) and two electrons to oxidized SCO1 [PMID:15199057, PMID:18458339], while SCO2 acts upstream as a thiol-disulfide oxidoreductase to set the redox state of SCO1's copper-coordinating cysteines, the two SCO proteins having non-overlapping cooperative roles [PMID:15229189, PMID:19336478]. Maturation occurs on a COX20-stabilized COX2 substrate presented to the SCO1/SCO2 module, and a fraction of SCO1 associates with assembled COX [PMID:19295170, PMID:24403053]. Beyond COX assembly, SCO1 governs cellular copper homeostasis through a mitochondrion-to-plasma-membrane signaling axis that maintains the copper importer CTR1 in a tissue-specific manner [PMID:17189203, PMID:25683716, PMID:28973536], and copper-loaded SCO1 tethers LKB1 to AMPK to activate AMPK signaling and promote mitochondrial biogenesis and fatty acid oxidation [PMID:36261001]. Pathogenic SCO1 mutations, including P174L which reduces Cu(I) affinity ~10,000-fold and impairs Cox17-mediated copper transfer, cause isolated COX deficiency and, in tissue-specific mouse models, dilated cardiomyopathy [PMID:11013136, PMID:17182746, PMID:16520371, PMID:28973536, PMID:40679281].","teleology":[{"year":1990,"claim":"Established that SCO1 acts after mitochondrial translation to protect nascent COX subunits, defining its role as a post-translational assembly factor rather than a transcription or translation factor.","evidence":"Yeast genetics with pulse-chase labeling of mitochondrial translation products, plus prior Northern analysis","pmids":["2835635","2173976"],"confidence":"Medium","gaps":["Did not identify the molecular activity of SCO1","No copper or partner protein implicated yet"]},{"year":1991,"claim":"Localized SCO1 to the inner mitochondrial membrane and showed its hydrophobic N-terminal anchor is essential, fixing where the protein acts.","evidence":"Subcellular fractionation, alkaline extraction, sucrose gradients, digitonin treatment, immunoblot in yeast","pmids":["1944230"],"confidence":"High","gaps":["Membrane topology relative to the COX assembly machinery not resolved","Biochemical activity still unknown"]},{"year":1996,"claim":"Placed SCO1 downstream of COX17 in mitochondrial copper delivery to cytochrome c oxidase and distinguished it functionally from SCO2.","evidence":"Yeast multicopy suppressor screen and genetic epistasis with null mutants","pmids":["8702795"],"confidence":"High","gaps":["Direct copper binding by SCO1 not yet demonstrated","Nature of SCO1/SCO2 cooperation undefined"]},{"year":1999,"claim":"Confirmed human SCO1 is the mitochondrial-targeted ortholog of yeast SCO1, transferring the pathway to mammals.","evidence":"In vitro import/protease-protection, EGFP imaging, and chimeric yeast complementation","pmids":["9878253","10218584"],"confidence":"Medium","gaps":["Full-length human protein did not complement yeast, leaving species-specific determinants unclear"]},{"year":2003,"claim":"Resolved the molecular function as Cu(I) coordination via a CXXXC motif and a conserved histidine and showed this binding is essential, establishing SCO1 as a copper metallochaperone with a thioredoxin-like fold.","evidence":"XAS/EXAFS and NMR structures of yeast and bacterial Sco with site-directed mutagenesis and yeast functional assays","pmids":["11546815","14604533"],"confidence":"High","gaps":["Copper donor and acceptor in vivo not yet biochemically demonstrated","Physiological relevance of Cu(II) binding unclear"]},{"year":2004,"claim":"Demonstrated direct, specific Cu(I) transfer from Cox17 to Sco1 and defined non-overlapping cooperative roles of SCO1 and SCO2 in human cells.","evidence":"In vitro copper transfer with purified proteins, Cox17 mutagenesis, yeast cytoplasmic metallation, and patient-cell rescue/dominant-negative assays","pmids":["15199057","15229189"],"confidence":"High","gaps":["Mechanistic basis of SCO1/SCO2 distinction not resolved","How copper is handed off to COX2 unknown"]},{"year":2003,"claim":"Pinpointed SCO1's step in COX assembly by showing a defined COX subassembly accumulates without MTCO2, indicating SCO1 is required for Cu(A) formation prior to MTCO2 incorporation.","evidence":"Blue native electrophoresis and immunoblot of subassemblies in SCO1-deficient patient fibroblasts","pmids":["14607829"],"confidence":"Medium","gaps":["Did not directly show copper delivery to MTCO2","Single-lab inference from loss-of-function"]},{"year":2006,"claim":"Provided high-resolution structural and quantitative basis for SCO1 function, including metal-induced conformational closing and the mechanistic defect of the P174L disease mutation (~10,000-fold reduced Cu(I) affinity).","evidence":"X-ray crystallography and NMR of apo/Cu/Ni forms, ESI-MS, KD measurements, in vitro transfer assays, and pulse-chase in patient fibroblasts","pmids":["15659396","16735468","16570183","17182746","16520371"],"confidence":"High","gaps":["SCO1 lacks detectable disulfide isomerase/peroxidase activity despite Trx-like fold, leaving the redox role ambiguous","Mechanism of H2O2 hypersensitivity unexplained"]},{"year":2008,"claim":"Defined the chemistry of copper handoff as a coupled copper-electron transfer in which oxidized Cox17 simultaneously transfers Cu(I) and two electrons to oxidized SCO1, explaining why SCO2 cannot perform this reaction.","evidence":"In vitro reconstitution with defined redox states, NMR, and thermodynamic analysis","pmids":["18458339"],"confidence":"High","gaps":["The downstream transfer to COX2 not reconstituted","In vivo redox cycling kinetics unknown"]},{"year":2009,"claim":"Ordered SCO2 upstream of SCO1, identifying SCO2 as a thiol-disulfide oxidoreductase that sets the redox state of SCO1's copper-coordinating cysteines, and showed a fraction of SCO1 associates with assembled COX.","evidence":"Mitochondrial pulse-labeling, RNAi, cysteine redox-state analysis in patient fibroblasts, BN-PAGE and Co-IP from muscle mitochondria","pmids":["19336478","19295170"],"confidence":"High","gaps":["Structural details of the SCO1-SCO2 functional complex not resolved","Oligomerization state regulation incompletely defined"]},{"year":2014,"claim":"Positioned the SCO1/SCO2 module within a COX20-dependent maturation pathway acting on newly synthesized, COX20-bound COX2.","evidence":"siRNA, TALEN knockout, and Co-IP of COX20-FLAG with newly synthesized COX2 plus subassembly analysis","pmids":["24403053"],"confidence":"High","gaps":["Stoichiometry and dynamics of the COX20-SCO1-SCO2 module unknown"]},{"year":2017,"claim":"Extended SCO1 function beyond COX assembly to cellular copper homeostasis, showing SCO1 maintains CTR1 via a mitochondrion-to-plasma-membrane signaling axis with tissue-specific consequences while mitochondrial copper pools are prioritized.","evidence":"Patient fibroblasts, shRNA, copper efflux/uptake and sensor measurements, conditional and tissue-specific Sco1 knockout/knockin mice, proteasome inhibition, CTR1 immunofluorescence","pmids":["17189203","21563821","25683716","28973536"],"confidence":"High","gaps":["The molecular signal relaying SCO1 status to CTR1 is unidentified","Why CTR1 is degraded in liver but mislocalized in heart is unexplained"]},{"year":2022,"claim":"Identified a copper-dependent signaling role in which copper-loaded SCO1 tethers LKB1 to AMPK, coupling mitochondrial copper status to AMPK activation, mitochondrial biogenesis, and fatty acid oxidation.","evidence":"Co-IP, SCO1 knockout/overexpression in mice and cells, AMPK activity assays, copper restoration","pmids":["36261001"],"confidence":"Medium","gaps":["Direct structural basis of the copper-dependent LKB1-AMPK tethering not resolved","Single-lab; reciprocal validation of the complex limited"]},{"year":2025,"claim":"Dissected tissue-specific SCO1 mechanisms, showing the heart is most susceptible to loss-of-function with combined COX and copper deficiency, while brain knockout produces COX deficiency without copper depletion.","evidence":"Brain-specific knockout and whole-body knockin (G115S, P157L, M277V) mice with COX activity and mitochondrial copper measurements","pmids":["40679281"],"confidence":"High","gaps":["Molecular basis of differential tissue susceptibility not resolved","How copper-handling and COX-assembly functions are separately weighted per tissue is unclear"]},{"year":null,"claim":"How copper is transferred from SCO1 to the Cu(A) site of COX2, and how the mitochondrial SCO1 status is mechanistically transmitted to the plasma membrane to control CTR1, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No reconstituted SCO1-to-COX2 copper transfer","Identity of the mitochondrion-to-membrane signal unknown","Connection between metallochaperone and AMPK/insulin signaling roles incompletely integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[8,11,13,20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[25,28]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[5,6]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[19,28]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[10,24]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[19,25]}],"complexes":["COX20-SCO1-SCO2 COX2 maturation module","SCO1-LKB1-AMPK complex","cytochrome c oxidase (COX)"],"partners":["COX17","SCO2","COX2","COX20","CTR1","LKB1","AMPK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75880","full_name":"Cytochrome c oxidase assembly factor SCO1","aliases":[],"length_aa":301,"mass_kda":33.8,"function":"Copper metallochaperone essential for the maturation of cytochrome c oxidase subunit II (MT-CO2/COX2). Together with SCO2, involved in delivering copper to the Cu(A) site on MT-CO2/COX2 (PubMed:15229189, PubMed:15659396, PubMed:16735468, PubMed:17189203, PubMed:19336478). Plays an important role in the regulation of copper homeostasis by controlling the abundance and cell membrane localization of copper transporter CTR1 (By similarity)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/O75880/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SCO1","classification":"Not Classified","n_dependent_lines":264,"n_total_lines":1208,"dependency_fraction":0.2185430463576159},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SCO1","total_profiled":1310},"omim":[{"mim_id":"619048","title":"MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 4; MC4DN4","url":"https://www.omim.org/entry/619048"},{"mim_id":"618064","title":"CYTOCHROME c OXIDASE ASSEMBLY FACTOR 16; COX16","url":"https://www.omim.org/entry/618064"},{"mim_id":"614772","title":"CYTOCHROME c OXIDASE ASSEMBLY FACTOR 6; COA6","url":"https://www.omim.org/entry/614772"},{"mim_id":"614698","title":"CYTOCHROME c OXIDASE ASSEMBLY FACTOR COX20; COX20","url":"https://www.omim.org/entry/614698"},{"mim_id":"604813","title":"CYTOCHROME c OXIDASE COPPER CHAPERONE COX17; COX17","url":"https://www.omim.org/entry/604813"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SCO1"},"hgnc":{"alias_symbol":[],"prev_symbol":["SCOD1"]},"alphafold":{"accession":"O75880","domains":[{"cath_id":"3.40.30.10","chopping":"142-299","consensus_level":"high","plddt":94.2411,"start":142,"end":299}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75880","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75880-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75880-F1-predicted_aligned_error_v6.png","plddt_mean":77.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SCO1","jax_strain_url":"https://www.jax.org/strain/search?query=SCO1"},"sequence":{"accession":"O75880","fasta_url":"https://rest.uniprot.org/uniprotkb/O75880.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75880/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75880"}},"corpus_meta":[{"pmid":"11013136","id":"PMC_11013136","title":"Mutations of the SCO1 gene in 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Northern blot showed normal transcription/mRNA maturation of OXI1, but CoxII protein was strongly reduced in sco1-1 mutant, indicating SCO1 acts post-transcriptionally.\",\n      \"method\": \"Yeast genetic analysis, mitochondrial translation product analysis, Northern blot hybridization\",\n      \"journal\": \"Molecular & general genetics : MGG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with specific molecular phenotype, multiple analytical methods, single lab\",\n      \"pmids\": [\"2835635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"Yeast SCO1 encodes a 33 kDa protein that is imported into mitochondria and processed to a 30 kDa form tightly associated with the mitochondrial membrane, as shown by in vitro transcription/translation and mitochondrial import assays.\",\n      \"method\": \"In vitro transcription/translation, mitochondrial import assay, protease protection\",\n      \"journal\": \"Molecular & general genetics : MGG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical import and fractionation experiments, single lab, two orthogonal methods\",\n      \"pmids\": [\"2543907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"SCO1 protein is required for a post-translational step: SCO1-deleted yeast translates CoxI and CoxII normally but the newly synthesized subunits are preferentially degraded, indicating SCO1 protects them from proteolysis during assembly.\",\n      \"method\": \"Yeast genetics, pulse-chase labeling of mitochondrial translation products\",\n      \"journal\": \"Current genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulse-chase establishes post-translational mechanism, single lab\",\n      \"pmids\": [\"2173976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Yeast SCO1 protein localizes to the inner mitochondrial membrane as an integral membrane protein; membrane localization is mediated by a 17-amino-acid hydrophobic N-terminal segment, and removal of this segment abolishes both membrane binding and biological function.\",\n      \"method\": \"Subcellular fractionation, alkaline extraction, isopycnic sucrose gradient centrifugation, digitonin treatment, immunoblot with anti-SCO1 antibodies\",\n      \"journal\": \"Molecular & general genetics : MGG\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical fractionation methods, functional consequence of domain deletion demonstrated\",\n      \"pmids\": [\"1944230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"SCO1 and SCO2 act as high-copy suppressors of a COX17 copper-recruitment defect in yeast; SCO1 overexpression compensates for the absence of Cox17p, placing SCO1 downstream of COX17 in the mitochondrial copper delivery pathway to cytochrome c oxidase. SCO2 cannot suppress a sco1 null mutant, indicating non-identical functions.\",\n      \"method\": \"Yeast multicopy suppressor screen, genetic epistasis, null mutant complementation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple alleles and null mutants, clearly positions SCO1 in copper delivery pathway downstream of COX17\",\n      \"pmids\": [\"8702795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human SCO1 is the ortholog of yeast SCO1; the human protein contains conserved functional domains and is imported into mitochondria as shown by in vitro import and protease-protection assays.\",\n      \"method\": \"Sequence alignment, in vitro mitochondrial import assay, protease-protection assay\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical import assay with protease protection, single lab\",\n      \"pmids\": [\"9878253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Both human SCO1 homologs (chromosomes 17 and 22) localize to mitochondria in HeLa cells when expressed as EGFP fusions; a chimera of the N-terminal half of yeast Sco1p and the C-terminal half of human chromosome-17 SCO1 complements the yeast sco1 deletion, but neither full-length human protein alone does.\",\n      \"method\": \"EGFP fusion live-cell imaging, yeast complementation assay with chimeric proteins\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by fluorescence imaging, complementation functional assay, single lab\",\n      \"pmids\": [\"10218584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Pathogenic mutations in human SCO1 (2-bp frameshift and P174L missense in the conserved CxxxC copper-binding domain) cause isolated COX deficiency; the P174L mutation affects a conserved proline adjacent to the CxxxC copper-binding domain, likely disrupting its tertiary structure.\",\n      \"method\": \"Mutation screening, compound heterozygosity analysis, sequence conservation analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — human genetics with structural inference, multiple mutations identified, replicated across patients\",\n      \"pmids\": [\"11013136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Purified C-terminal domain of yeast Sco1 binds one Cu(I) per monomer via three ligands—two conserved cysteines in the CXXXC motif and a conserved histidine—as shown by X-ray absorption spectroscopy. Mutation of any one of these residues abolishes Sco1 function in yeast.\",\n      \"method\": \"Protein purification, X-ray absorption spectroscopy (XAS/EXAFS), site-directed mutagenesis, yeast functional assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical characterization with XAS, mutagenesis validated in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"11546815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Solution structure of Sco1 from Bacillus subtilis (NMR) reveals a thioredoxin-like fold with the copper-binding CXXXCP motif positioned analogously to the catalytic residues in thioredoxins; in vitro binding shows Cu(I) coordinated through CXXXCP and His135, and Cu(II) binding also occurs but appears adventitious.\",\n      \"method\": \"NMR structure determination, in vitro copper binding\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with in vitro copper binding characterization, bacterial ortholog structurally consistent with mammalian SCO1\",\n      \"pmids\": [\"14604533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In SCO1-deficient patient fibroblasts, a COX subassembly containing MTCO1, COX4, and COX5A accumulates, indicating that SCO1 function is required for the subsequent association of MTCO2 with this subassembly (i.e., Cu(A) center formation in MTCO2 precedes MTCO2 incorporation into the assembly line).\",\n      \"method\": \"Blue native gel electrophoresis, immunoblot of COX subassemblies from patient fibroblasts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — native gel with pathway inference in loss-of-function patient cells, single lab\",\n      \"pmids\": [\"14607829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Cox17 directly and specifically transfers Cu(I) to both Sco1 and Cox11 in vitro using purified proteins; a C57Y mutant of Cox17 fails to transfer copper to Sco1 but retains ability to transfer to Cox11, demonstrating distinct transfer mechanisms. Metallation of cytoplasmic Sco1 in yeast is strictly dependent on co-expression of Cox17.\",\n      \"method\": \"In vitro copper transfer assay with purified proteins, yeast cytoplasmic expression system, Cox17 mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro copper transfer, mutagenesis, and in vivo yeast corroboration; multiple orthogonal methods\",\n      \"pmids\": [\"15199057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human SCO1 and SCO2 have non-overlapping cooperative functions: COX17 overexpression rescues COX deficiency in SCO2 but not SCO1 patient cells; overexpression of either SCO protein in the reciprocal patient background produces a dominant-negative phenotype suggesting physical interaction. SCO1 and SCO2 function as homodimers by size-exclusion chromatography. The dominant-negative effect in SCO2 background maps to the N-terminal domain of SCO1.\",\n      \"method\": \"Patient cell lines, overexpression rescue/dominant-negative assays, chimeric protein complementation, size-exclusion chromatography\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional approaches in patient cells, epistasis defined, dominant-negative domain mapping, single lab with comprehensive analysis\",\n      \"pmids\": [\"15229189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human Sco1 and Sco2 each bind Cu(I) (trigonal coordination) and Cu(II) (type II-like, higher coordination); Cu(I) binding requires two conserved cysteines and a histidine. Asp238 in human Sco1 is required for Cu(II) binding and normal in vivo function. Metallation of human Sco1 in yeast cytoplasm depends on co-expression of human Cox17, but Sco2 metallation does not.\",\n      \"method\": \"Protein expression in bacteria and yeast, X-ray absorption spectroscopy, site-directed mutagenesis, yeast functional assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple spectroscopic and mutagenesis methods, in vivo functional validation, two copper-binding modes characterized\",\n      \"pmids\": [\"16091356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of human SCO1 (apo form, 2.8 Å) reveals a thioredoxin/peroxiredoxin-like fold with putative copper-binding ligands at positions equivalent to catalytic residues in Trx/Prx; SCO1 does not possess disulfide isomerization or peroxidase activity, but both human SCO1 and yeast sco1 null show extreme sensitivity to H2O2.\",\n      \"method\": \"X-ray crystallography, enzymatic activity assays (disulfide isomerization, peroxidase), H2O2 sensitivity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional activity assays in both human and yeast, multiple methods\",\n      \"pmids\": [\"15659396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Solution structures of apo, Cu(I), and Ni(II) forms of human Sco1 (NMR) reveal that metal binding shifts the protein from an open, conformationally mobile state to a closed, rigid conformation. Cu(I) is coordinated by two Cys of the CPXXCP motif and a His residue. The Ni(II)-bound structure suggests the protein may also retain thioredoxin-like function in oxidized form.\",\n      \"method\": \"NMR structure determination, electrospray ionization mass spectrometry, X-ray crystallography of Ni(II) form\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple structures (apo, Cu(I), Ni(II)) by NMR and crystallography, conformational change characterized by ESI-MS\",\n      \"pmids\": [\"16735468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structures of yeast apo-Sco1 (1.8 Å) and Cu-Sco1 (2.3 Å) show a thioredoxin-like fold; the conserved His239 is on a flexible 'Sco loop' proximal to both cysteine pairs; an unexpected copper-binding site involving non-conserved Cys181/Cys216 is observed in the soaked crystal. Electrostatic surface analysis suggests interaction sites with Cox17 and COX2.\",\n      \"method\": \"X-ray crystallography, copper soaking experiments\",\n      \"journal\": \"Journal of biological inorganic chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structures of both apo and copper-loaded forms, ortholog consistent with mammalian gene function\",\n      \"pmids\": [\"16570183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The P174L pathogenic mutation of human Sco1 reduces Cu(I) binding affinity ~10,000-fold (KD ~10^-13 vs ~10^-17 M for wild-type), and impairs the transient Cox17/Cu(I)/Sco1 complex formation and copper transfer from Cu(I)Cox17 to Sco1, without abolishing copper binding entirely.\",\n      \"method\": \"NMR solution structure of mutant, Cu(I) affinity measurements, in vitro copper transfer assays, Cox17 interaction studies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structure, affinity measurement, and transfer assay combined in one study with quantitative KD values\",\n      \"pmids\": [\"17182746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The P174L mutation in human Sco1 retains normal Cu(I) and Cu(II) binding when expressed in bacteria, but Cox17-mediated copper transfer to Sco1 is severely compromised both in vitro and in a yeast cytoplasmic assay. Pulse-chase labeling in SCO1 patient fibroblasts shows normal CoxII translation rate but rapid and specific turnover of newly synthesized CoxII.\",\n      \"method\": \"Protein expression and metal binding analysis, in vitro copper transfer assay, yeast cytoplasmic assay, pulse-chase labeling in patient fibroblasts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted transfer assay, yeast assay, and pulse-chase in patient cells; comprehensive multi-method analysis\",\n      \"pmids\": [\"16520371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human SCO1 and SCO2 have additional roles in cellular copper homeostasis beyond COX assembly; mutations in either SCO result in tissue- and allele-specific cellular copper deficiency that can be dissociated from COX assembly defects. The copper deficiency reflects increased copper efflux, not decreased uptake, and is suppressed by SCO2 overexpression but not SCO1 overexpression.\",\n      \"method\": \"Patient cell lines, shRNA knockdown, copper efflux/uptake measurements, SCO overexpression rescue\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple patient backgrounds, shRNA controls, dissection of uptake vs. efflux, rescue experiments; comprehensive mechanistic dissection\",\n      \"pmids\": [\"17189203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cu(I)HCox17 (partially oxidized, 2S-S form) simultaneously transfers Cu(I) and two electrons to oxidized HSco1 (disulfide form), yielding Cu(I)HSco1 and fully oxidized apoHCox17; the reaction is thermodynamically driven by copper transfer. This coupled copper-electron transfer does not occur with HSco2 due to absence of a specific metal-bridged protein-protein complex.\",\n      \"method\": \"In vitro reconstitution with purified proteins, redox chemistry, NMR, thermodynamic analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with defined redox states, thermodynamic measurements, mechanistic distinction between Sco1 and Sco2\",\n      \"pmids\": [\"18458339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SCO2 acts upstream of SCO1 in COX assembly: pulse-labeling shows COX II synthesis is reduced in SCO2 but not SCO1 patient cells; RNAi of mutant SCO2 abolishes COX II labeling. SCO2 acts as a thiol-disulfide oxidoreductase to oxidize the copper-coordinating cysteines in SCO1 during COX II maturation; the ratio of oxidized to reduced cysteines in SCO1 is perturbed in both SCO patient backgrounds and is corrected by SCO2 overexpression or knockdown.\",\n      \"method\": \"Mitochondrial translation pulse-labeling, RNAi knockdown, cysteine redox state analysis in patient fibroblasts, overexpression rescue\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pulse-labeling defines upstream/downstream order, RNAi confirms, redox state of SCO1 cysteines directly measured; multiple orthogonal methods\",\n      \"pmids\": [\"19336478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A fraction of Sco1 physically associates with the assembled COX complex in human muscle mitochondria as shown by blue native immunoblot and co-immunoprecipitation. The G132S mutation in SCO1 causes the protein to migrate exclusively as a monomer rather than a higher-order form, indicating the mutation disrupts oligomerization.\",\n      \"method\": \"Blue native gel electrophoresis, co-immunoprecipitation from human muscle mitochondria\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal methods (BN-PAGE + Co-IP) in patient and control tissue, single lab\",\n      \"pmids\": [\"19295170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Despite global copper deficiency at the whole-cell level in SCO1 and SCO2 patient fibroblasts, total and exchangeable mitochondrial Cu(+) pools are largely maintained at normal levels, demonstrating that cells prioritize mitochondrial copper homeostasis even when SCO metallochaperones are dysfunctional.\",\n      \"method\": \"Fluorescent mitochondria-targeted copper sensor (Mito-CS1) live imaging, biochemical copper measurements in patient fibroblasts\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — targeted fluorescent sensor with biochemical validation, patient fibroblast model, single lab\",\n      \"pmids\": [\"21563821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"COX20 interacts with newly synthesized COX2, and SCO1 and SCO2 act on COX20-bound COX2; COX20 acts as a chaperone stabilizing newly synthesized COX2 and presenting it to the SCO1/SCO2 metallochaperone module for Cu(A) site maturation prior to COX2 incorporation into early COX subassemblies.\",\n      \"method\": \"siRNA knockdown, TALEN knockout, immunoprecipitation of COX20-FLAG with newly synthesized COX2, subassembly analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP defines order of assembly, knockout cell lines, multiple loss-of-function approaches, pathway position established\",\n      \"pmids\": [\"24403053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SCO1 is required to maintain CTR1 (the high-affinity copper importer) protein at steady-state levels; in Sco1-/- mouse embryonic fibroblasts, CTR1 is rapidly degraded and its levels are restored by proteasome inhibition, establishing a post-translational mitochondrial-to-plasma-membrane signaling axis through SCO1 that regulates cellular copper import.\",\n      \"method\": \"Liver-specific Sco1 knockout mice, immunoblot, proteasome inhibitor treatment in MEFs\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout mouse model, proteasome inhibitor rescue, mechanistic pathway established in vivo and in cells\",\n      \"pmids\": [\"25683716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In the heart, SCO1 maintains CTR1 at the plasma membrane; cardiac-specific and striated-muscle-specific Sco1 deletion causes dilated cardiomyopathy with combined COX and copper deficiency, and CTR1 is mislocalised to the cytosol rather than degraded (unlike in liver), demonstrating tissue-specific consequences of SCO1 loss on CTR1 regulation.\",\n      \"method\": \"Heart- and striated-muscle-specific Sco1 knockout and knockin (G115S) mice, immunofluorescence for CTR1 localization, COX activity assays, copper measurements\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple tissue-specific mouse models including knockin, direct CTR1 localization imaging, functional COX and copper measurements\",\n      \"pmids\": [\"28973536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SCO1 overexpression in adipocytes leads to intracellular copper deficiency, and this copper loss causes insulin resistance by increasing PTEN protein levels; addition of exogenous copper abolishes the insulin resistance caused by SCO1 overexpression, establishing SCO1 as a regulator of insulin sensitivity via copper levels in white adipose tissue.\",\n      \"method\": \"Overexpression in adipocytes, copper supplementation rescue, PTEN protein measurement, insulin sensitivity assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single overexpression approach, mechanistic connection to PTEN is indirect\",\n      \"pmids\": [\"28647369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Copper-loaded SCO1 directly interacts with LKB1 and tethers LKB1 to AMPK, thereby activating AMPK and promoting mitochondrial biogenesis and fatty acid oxidation; SCO1 constitutively interacts with LKB1 even without copper, but copper loading is required for AMPK tethering and activation.\",\n      \"method\": \"Co-immunoprecipitation, SCO1 knockout and overexpression in mice and cells, AMPK activity assays, copper restoration experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP defines SCO1-LKB1-AMPK complex, in vivo mouse model, copper-dependence established, single lab\",\n      \"pmids\": [\"36261001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In an isogenic murine background, the heart is the most susceptible organ to SCO1 loss-of-function; Sco1G115S and Sco1P157L knockin hearts develop dilated cardiomyopathy with combined COX and copper deficiency including mitochondrial copper pool depletion, while brain-specific Sco1 knockout causes severe COX deficiency without altered copper content, demonstrating tissue-specific mechanisms of SCO1 function.\",\n      \"method\": \"Brain-specific Sco1 knockout mice, whole-body SCO1 knockin mice (G115S, P157L, M277V), COX activity assays, copper content measurements (including mitochondrial copper pool)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple knockin alleles and tissue-specific knockouts in isogenic background, comprehensive phenotyping dissecting COX vs. copper functions by tissue\",\n      \"pmids\": [\"40679281\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SCO1 is a mitochondrial inner membrane metallochaperone that, after receiving Cu(I) from Cox17 (via a coupled copper-electron transfer reaction), delivers copper to the Cu(A) site of cytochrome c oxidase subunit COX2 in cooperation with SCO2 (which acts upstream as a thiol-disulfide oxidoreductase to prepare SCO1's copper-coordinating cysteines); SCO1 also forms part of a COX20-SCO1-SCO2 maturation module for newly synthesized COX2, physically associates with assembled COX complex, and additionally signals from mitochondria to the plasma membrane to regulate CTR1-dependent cellular copper import and, through a copper-loaded SCO1-LKB1-AMPK complex, modulates cellular energy metabolism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SCO1 is a copper-binding inner mitochondrial membrane metallochaperone that delivers copper to the Cu(A) site of cytochrome c oxidase subunit COX2, a function conserved from yeast to humans [#4, #5, #8]. It is anchored as an integral inner-membrane protein via an N-terminal hydrophobic segment required for both membrane binding and function [#3], and acts post-transcriptionally and post-translationally to protect and mature newly synthesized COX2, whose Cu(A) center must form before COX2 incorporates into the assembly line [#0, #2, #10]. SCO1 adopts a thioredoxin-like fold and coordinates one Cu(I) per monomer through two cysteines of a CXXXC(P) motif and a conserved histidine, transitioning from an open to a closed conformation upon metal binding [#8, #9, #15, #16]. It receives copper from Cox17 through a coupled copper-electron transfer reaction in which partially oxidized Cu(I)Cox17 simultaneously transfers Cu(I) and two electrons to oxidized SCO1 [#11, #20], while SCO2 acts upstream as a thiol-disulfide oxidoreductase to set the redox state of SCO1's copper-coordinating cysteines, the two SCO proteins having non-overlapping cooperative roles [#12, #21]. Maturation occurs on a COX20-stabilized COX2 substrate presented to the SCO1/SCO2 module, and a fraction of SCO1 associates with assembled COX [#22, #24]. Beyond COX assembly, SCO1 governs cellular copper homeostasis through a mitochondrion-to-plasma-membrane signaling axis that maintains the copper importer CTR1 in a tissue-specific manner [#19, #25, #26], and copper-loaded SCO1 tethers LKB1 to AMPK to activate AMPK signaling and promote mitochondrial biogenesis and fatty acid oxidation [#28]. Pathogenic SCO1 mutations, including P174L which reduces Cu(I) affinity ~10,000-fold and impairs Cox17-mediated copper transfer, cause isolated COX deficiency and, in tissue-specific mouse models, dilated cardiomyopathy [#7, #17, #18, #26, #29].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established that SCO1 acts after mitochondrial translation to protect nascent COX subunits, defining its role as a post-translational assembly factor rather than a transcription or translation factor.\",\n      \"evidence\": \"Yeast genetics with pulse-chase labeling of mitochondrial translation products, plus prior Northern analysis\",\n      \"pmids\": [\"2835635\", \"2173976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the molecular activity of SCO1\", \"No copper or partner protein implicated yet\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Localized SCO1 to the inner mitochondrial membrane and showed its hydrophobic N-terminal anchor is essential, fixing where the protein acts.\",\n      \"evidence\": \"Subcellular fractionation, alkaline extraction, sucrose gradients, digitonin treatment, immunoblot in yeast\",\n      \"pmids\": [\"1944230\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Membrane topology relative to the COX assembly machinery not resolved\", \"Biochemical activity still unknown\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Placed SCO1 downstream of COX17 in mitochondrial copper delivery to cytochrome c oxidase and distinguished it functionally from SCO2.\",\n      \"evidence\": \"Yeast multicopy suppressor screen and genetic epistasis with null mutants\",\n      \"pmids\": [\"8702795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct copper binding by SCO1 not yet demonstrated\", \"Nature of SCO1/SCO2 cooperation undefined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Confirmed human SCO1 is the mitochondrial-targeted ortholog of yeast SCO1, transferring the pathway to mammals.\",\n      \"evidence\": \"In vitro import/protease-protection, EGFP imaging, and chimeric yeast complementation\",\n      \"pmids\": [\"9878253\", \"10218584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full-length human protein did not complement yeast, leaving species-specific determinants unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved the molecular function as Cu(I) coordination via a CXXXC motif and a conserved histidine and showed this binding is essential, establishing SCO1 as a copper metallochaperone with a thioredoxin-like fold.\",\n      \"evidence\": \"XAS/EXAFS and NMR structures of yeast and bacterial Sco with site-directed mutagenesis and yeast functional assays\",\n      \"pmids\": [\"11546815\", \"14604533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Copper donor and acceptor in vivo not yet biochemically demonstrated\", \"Physiological relevance of Cu(II) binding unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated direct, specific Cu(I) transfer from Cox17 to Sco1 and defined non-overlapping cooperative roles of SCO1 and SCO2 in human cells.\",\n      \"evidence\": \"In vitro copper transfer with purified proteins, Cox17 mutagenesis, yeast cytoplasmic metallation, and patient-cell rescue/dominant-negative assays\",\n      \"pmids\": [\"15199057\", \"15229189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic basis of SCO1/SCO2 distinction not resolved\", \"How copper is handed off to COX2 unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Pinpointed SCO1's step in COX assembly by showing a defined COX subassembly accumulates without MTCO2, indicating SCO1 is required for Cu(A) formation prior to MTCO2 incorporation.\",\n      \"evidence\": \"Blue native electrophoresis and immunoblot of subassemblies in SCO1-deficient patient fibroblasts\",\n      \"pmids\": [\"14607829\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not directly show copper delivery to MTCO2\", \"Single-lab inference from loss-of-function\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided high-resolution structural and quantitative basis for SCO1 function, including metal-induced conformational closing and the mechanistic defect of the P174L disease mutation (~10,000-fold reduced Cu(I) affinity).\",\n      \"evidence\": \"X-ray crystallography and NMR of apo/Cu/Ni forms, ESI-MS, KD measurements, in vitro transfer assays, and pulse-chase in patient fibroblasts\",\n      \"pmids\": [\"15659396\", \"16735468\", \"16570183\", \"17182746\", \"16520371\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SCO1 lacks detectable disulfide isomerase/peroxidase activity despite Trx-like fold, leaving the redox role ambiguous\", \"Mechanism of H2O2 hypersensitivity unexplained\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the chemistry of copper handoff as a coupled copper-electron transfer in which oxidized Cox17 simultaneously transfers Cu(I) and two electrons to oxidized SCO1, explaining why SCO2 cannot perform this reaction.\",\n      \"evidence\": \"In vitro reconstitution with defined redox states, NMR, and thermodynamic analysis\",\n      \"pmids\": [\"18458339\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The downstream transfer to COX2 not reconstituted\", \"In vivo redox cycling kinetics unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Ordered SCO2 upstream of SCO1, identifying SCO2 as a thiol-disulfide oxidoreductase that sets the redox state of SCO1's copper-coordinating cysteines, and showed a fraction of SCO1 associates with assembled COX.\",\n      \"evidence\": \"Mitochondrial pulse-labeling, RNAi, cysteine redox-state analysis in patient fibroblasts, BN-PAGE and Co-IP from muscle mitochondria\",\n      \"pmids\": [\"19336478\", \"19295170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural details of the SCO1-SCO2 functional complex not resolved\", \"Oligomerization state regulation incompletely defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Positioned the SCO1/SCO2 module within a COX20-dependent maturation pathway acting on newly synthesized, COX20-bound COX2.\",\n      \"evidence\": \"siRNA, TALEN knockout, and Co-IP of COX20-FLAG with newly synthesized COX2 plus subassembly analysis\",\n      \"pmids\": [\"24403053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics of the COX20-SCO1-SCO2 module unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended SCO1 function beyond COX assembly to cellular copper homeostasis, showing SCO1 maintains CTR1 via a mitochondrion-to-plasma-membrane signaling axis with tissue-specific consequences while mitochondrial copper pools are prioritized.\",\n      \"evidence\": \"Patient fibroblasts, shRNA, copper efflux/uptake and sensor measurements, conditional and tissue-specific Sco1 knockout/knockin mice, proteasome inhibition, CTR1 immunofluorescence\",\n      \"pmids\": [\"17189203\", \"21563821\", \"25683716\", \"28973536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The molecular signal relaying SCO1 status to CTR1 is unidentified\", \"Why CTR1 is degraded in liver but mislocalized in heart is unexplained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a copper-dependent signaling role in which copper-loaded SCO1 tethers LKB1 to AMPK, coupling mitochondrial copper status to AMPK activation, mitochondrial biogenesis, and fatty acid oxidation.\",\n      \"evidence\": \"Co-IP, SCO1 knockout/overexpression in mice and cells, AMPK activity assays, copper restoration\",\n      \"pmids\": [\"36261001\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct structural basis of the copper-dependent LKB1-AMPK tethering not resolved\", \"Single-lab; reciprocal validation of the complex limited\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Dissected tissue-specific SCO1 mechanisms, showing the heart is most susceptible to loss-of-function with combined COX and copper deficiency, while brain knockout produces COX deficiency without copper depletion.\",\n      \"evidence\": \"Brain-specific knockout and whole-body knockin (G115S, P157L, M277V) mice with COX activity and mitochondrial copper measurements\",\n      \"pmids\": [\"40679281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of differential tissue susceptibility not resolved\", \"How copper-handling and COX-assembly functions are separately weighted per tissue is unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How copper is transferred from SCO1 to the Cu(A) site of COX2, and how the mitochondrial SCO1 status is mechanistically transmitted to the plasma membrane to control CTR1, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No reconstituted SCO1-to-COX2 copper transfer\", \"Identity of the mitochondrion-to-membrane signal unknown\", \"Connection between metallochaperone and AMPK/insulin signaling roles incompletely integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [8, 11, 13, 20]},\n      {\"term_id\": \"GO:0046872\", \"supporting_discovery_ids\": [8, 9, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [25, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005743\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [19, 28]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [10, 24]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [19, 25]}\n    ],\n    \"complexes\": [\n      \"COX20-SCO1-SCO2 COX2 maturation module\",\n      \"SCO1-LKB1-AMPK complex\",\n      \"cytochrome c oxidase (COX)\"\n    ],\n    \"partners\": [\n      \"COX17\",\n      \"SCO2\",\n      \"COX2\",\n      \"COX20\",\n      \"CTR1\",\n      \"LKB1\",\n      \"AMPK\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}