Gene Ontology annotation through association of InterPro records with GO terms
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
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UniProtKB keyword-to-GO mappings (e.g., Metal-binding, Mitochondrion, Copper) produce broad IEA annotations such as metal ion binding and cytochrome complex assembly for SCO2.
Gene Ontology annotation based on curation of immunofluorescence data
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene.
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SCO2 was identified as a nuclear COX assembly gene whose recessive mutations cause fatal infantile cardioencephalomyopathy with COX deficiency.
"we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency"
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The enzymatic deficiency caused by SCO2 mutations is most severe in cardiac and skeletal muscle and results from loss of mtDNA-encoded COX subunits, implicating SCO2 in COX holoenzyme assembly rather than catalysis.
"Immunohistochemical studies implied that the enzymatic deficiency, which was most severe in cardiac and skeletal muscle, was due to the loss of mtDNA-encoded COX subunits."
Human SCO1 and SCO2 have independent, cooperative functions in copper delivery to cytochrome c oxidase.
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SCO1 and SCO2 are paralogous metallochaperones that have independent but cooperative functions in delivering copper to the CuA site of cytochrome c oxidase.
"Human SCO1 and SCO2 are paralogous genes that code for metallochaperone proteins with essential, but poorly understood, roles in copper delivery to cytochrome c oxidase (COX)."
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SCO2 patient cells show a defect in COX assembly with accumulation of a common assembly intermediate, demonstrating the role of SCO2 in CIV assembly by mutant phenotype.
"Immunoblot analysis of patient cell lines showed reduced levels of the mutant proteins, resulting in a defect in COX assembly, and the appearance of a common assembly intermediate."
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COX17 delivers copper to SCO2, which transfers it to the CuA site of COX2 in a reaction facilitated by SCO1, defining the SCO2-mediated step of the mitochondrial copper relay.
"We propose a model in which COX17 delivers copper to SCO2, which in turn transfers it directly to the CuA site at an early stage of COX assembly in a reaction that is facilitated by SCO1."
p53 regulates mitochondrial respiration.
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SCO2 is a transcriptional target of p53, and its expression couples p53 status to mitochondrial respiration; loss of SCO2 in p53 wild-type cancer cells reproduces the glycolytic (Warburg) phenotype of p53-deficient cells.
"Disruption of the SCO2 gene in human cancer cells with wild-type p53 recapitulated the metabolic switch toward glycolysis that is exhibited by p53-deficient cells."
Human SCO2 is required for the synthesis of CO II and as a thiol-disulphide oxidoreductase for SCO1.
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SCO2 acts upstream of SCO1 and is indispensable for synthesis of COX2 (CO II); subsequent COX2 maturation requires both SCO proteins with intact CXXXC copper-coordinating motifs.
"These results indicate that SCO2 acts upstream of SCO1, and that it is indispensable for CO II synthesis. The subsequent maturation of CO II is contingent upon the formation of a complex that includes both SCO proteins, each with a functional CxxxC copper-coordinating motif."
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SCO2 functions as a thiol-disulphide oxidoreductase that oxidizes the copper-coordinating cysteines of SCO1 during CuA site maturation.
"SCO2 acts as a thiol-disulphide oxidoreductase to oxidize the copper-coordinating cysteines in SCO1 during CO II maturation."
Unexpected vascular enrichment of SCO1 over SCO2 in mammalian tissues: implications for human mitochondrial disease.
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SCO1 and SCO2 show divergent tissue expression patterns in mammals (SCO1 enriched in liver and vasculature; SCO2 enriched in muscle), partially explaining the tissue specificity of SCO1- and SCO2-related mitochondrial disease phenotypes.
"the expression of SCO1, but not of SCO2, is very high in liver (the tissue most affected in SCO1-mutant patients), whereas the reverse holds true in muscle (the tissue most affected in SCO2-mutant patients)."
Mutations in SCO2 are associated with autosomal-dominant high-grade myopia.
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SCO2 mutations segregate with autosomal-dominant high-grade myopia (MYP6); SCO2 mRNA is down-regulated in myopic mouse retina and SCO2 protein is detected in retina, retinal pigment epithelium and sclera.
"Messenger RNA levels of SCO2 were significantly downregulated in myopic mouse retinae. Immunohistochemistry in mouse eyes confirmed SCO2 protein localization in retina, retinal pigment epithelium, and sclera."
Human COX20 cooperates with SCO1 and SCO2 to mature COX2 and promote the assembly of cytochrome c oxidase.
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COX20 acts as a chaperone for newly synthesized COX2, stabilizing it and presenting it to the SCO1/SCO2 metallochaperone module for CuA-site maturation and CIV assembly.
"We propose that COX20 acts as a chaperone in the early steps of COX2 maturation, stabilizing the newly synthesized protein and presenting COX2 to its metallochaperone module, which in turn facilitates the incorporation of mature COX2 into the CIV assembly line."
Cooperation between COA6 and SCO2 in COX2 maturation during cytochrome c oxidase assembly links two mitochondrial cardiomyopathies.
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COA6 is a constituent of the mitochondrial copper relay that physically interacts with SCO2; pathogenic mutations in either protein disrupt complex formation, mechanistically linking COA6- and SCO2-associated cardiomyopathies.
"We show that COA6 and SCO2 interact and that corresponding pathogenic mutations in each protein affect complex formation"
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COA6 functions in the metallation of COX2 during cytochrome c oxidase assembly and its loss converges on the same CuA-maturation pathway as SCO2 loss.
"Our analyses define COA6 as a constituent of the mitochondrial copper relay system, linking defects in COX2 metallation to cardiac cytochrome c oxidase deficiency."
Human mitochondrial cytochrome c oxidase assembly factor COX18 acts transiently as a membrane insertase within the subunit 2 maturation module.
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COX18 acts as a transient membrane insertase for the COX2 C-tail; on its release, the SCO1-SCO2-COA6 copper-metallation module binds the COX2-COX20 complex to finalize COX2 biogenesis.
"The release of COX18 from this complex coincides with the binding of the SCO1-SCO2-COA6 copper metallation module to COX2-COX20 to finalize COX2 biogenesis."
The mitochondrial TMEM177 associates with COX20 during COX2 biogenesis.
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TMEM177 associates with newly synthesized COX2 and SCO2 in a COX20-dependent manner, expanding the COX2 maturation interactome to include TMEM177 alongside the SCO1/SCO2/COA6 module.
"TMEM177 associates with newly synthesized COX2 and SCO2 in a COX20-dependent manner"
COX16 promotes COX2 metallation and assembly during respiratory complex IV biogenesis.
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COX16 interacts with newly synthesized COX2 and with its copper-center-forming metallochaperones SCO1, SCO2, and COA6, promoting COX2 metallation during CIV biogenesis.
"COX16, a protein required for cytochrome c oxidase assembly, interacts specifically with newly synthesized COX2 and its copper center-forming metallochaperones SCO1, SCO2, and COA6."
A reference map of the human binary protein interactome.
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Reports a high-throughput binary protein interactome (HI-Union) in which SCO2 was scored as interacting with CIDEB; in the absence of orthogonal validation or functional rationale this binding is treated as likely false-positive for SCO2 curation.
"A reference map of the human binary protein interactome."
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
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Quantitative mass-spectrometry-based mitochondrial proteomics confirms SCO2 as a bona fide mitochondrial protein and provides high-throughput evidence for its mitochondrion localization.
"Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context."
TP53 stimulates SCO2 gene transcription
Metallochaperone inserts Cu2+ into MT-CO1
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Reactome describes a nine-subunit metallochaperone complex (COA3, COA5, COX10, dimeric COX11, COX15, COX16, COX19, SCO1, SCO2) that inserts Cu2+ into MT-CO1; SCO2 is placed in this complex on the mitochondrial inner membrane.
"A metallochaperone complex consisting of nine subunits (COA3, COA5, COX10, dimeric COX11, COX15, COX16, COX19, SCO1, SCO2)"
MT-CO1 and MT-CO2 complexes associate, installing heme moieties
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Reactome places SCO2 with COA6, SCO1, COX10 and COX15 in the dynamic metallochaperone complex that mediates association of MT-CO1 and MT-CO2 modules and heme A installation during CIV assembly.
"A dynamic metallochaperone complex involving the heme A biosynthetic enzymes COX10 and COX15, together with COX2-specific copper chaperones COA6, SCO1, and SCO2"
Metallochaperone inserts 2Cu2+ into MT-CO2
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Reactome describes insertion of two Cu2+ ions (the CuA site) into MT-CO2 by the SCO2-containing metallochaperone complex, which is the most functionally relevant Reactome entry for SCO2's core role.
"A metallochaperone complex consisting of nine subunits (COA3, COA5, COX10, dimeric COX11, COX15, COX16, COX19, SCO1, SCO2) carries two copper cations ...to the pre-assembled MT-CO2 subunit. These copper ions are frequently called CuA"