Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
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PAINT/PANTHER phylogenetic annotation transfers experimentally validated Cox15 family functions (heme A synthase activity, mitochondrial inner membrane localization, heme A biosynthetic process) to human COX15.
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Gene Ontology annotation based on curation of immunofluorescence data
Combined Automated Annotation using Multiple IEA Methods
Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy.
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Biallelic COX15 mutations cause isolated cytochrome c oxidase deficiency presenting as fatal infantile hypertrophic cardiomyopathy, establishing COX15 as a human COX deficiency disease gene alongside SCO2.
"This study establishes COX15 as an additional cause, along with SCO2, of fatal infantile, hypertrophic cardiomyopathy associated with isolated COX deficiency."
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COX15-deficient tissues show reduced heme A and accumulated heme O, mechanistically placing COX15 at the heme O → heme A step of the heme A biosynthetic pathway.
"Mitochondrial heme A content was reduced in the patient's heart and fibroblast mitochondria, and levels of heme O were increased in the patient's heart."
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COX15 re-expression rescues heme A content and COX activity in patient fibroblasts, demonstrating by functional complementation that reduced heme A availability is what stalls COX assembly.
"Expression of COX15 increased heme A content and rescued COX activity. These results suggest that reduced availability of heme A stalls the assembly of COX."
Analysis of Oligomerization Properties of Heme a Synthase Provides Insights into Its Function in Eukaryotes.
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Eukaryotic Cox15 (heme A synthase) forms evolutionarily conserved homotypic complexes via hydrophobic interactions that are independent of heme levels and of catalytic activity, suggesting multimerization is a constitutive feature of the enzyme.
"Our results indicate that Cox15 exhibits homotypic interactions, forming highly stable complexes dependent upon hydrophobic interactions. This multimerization is evolutionarily conserved and independent of heme levels and heme a synthase catalytic activity."
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Four conserved histidines are essential for eukaryotic heme A synthase activity and cannot be substituted with other heme-ligating residues, consistent with their role in heme binding and catalysis.
"Four conserved histidine residues are demonstrated to be critical for eukaryotic heme a synthase activity and cannot be substituted with other heme-ligating amino acids."
A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration Reveals New Mechanisms of Redox Homeostasis and NF-κB Signaling.
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
Identification and characterization of human cDNAs specific to BCS1, PET112, SCO1, COX15, and COX11, five genes involved in the formation and function of the mitochondrial respiratory chain.
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The human COX15 cDNA was identified as an ortholog of yeast COX15 and shown by in vitro import / protease-protection assay to be mitochondrially targeted, providing the original experimental evidence for human COX15 mitochondrial localization.
"Mitochondrial targeting of the human gene products, suggested by computer analysis of the protein sequences, was confirmed by an in vitro import and protease-protection assay."
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Sequence comparison shows extensive identity/similarity with yeast Cox15, including conservation of functional domains, justifying transfer of yeast Cox15 heme A synthase function to the human ortholog.
"Significant amino acid identity and similarity were demonstrated by comparison of the human with the corresponding yeast polypeptides. Sequence alignment revealed numerous colinear identical regions and the conservation of functional domains."
COX15 transforms heme O to heme A
Metallochaperone inserts Cu2+ into MT-CO1
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Reactome places COX15 in a nine-subunit metallochaperone/biogenesis complex (COA3, COA5, COX10, dimeric COX11, COX15, COX16, COX19, SCO1, SCO2) that delivers Cu2+ to MT-CO1 during CIV assembly, coupling heme A supply to copper insertion.
MT-CO1 and MT-CO2 complexes associate, installing heme moieties
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Reactome describes a dynamic metallochaperone complex including the heme A biosynthetic enzymes COX10 and COX15 alongside COX2 copper chaperones (COA6, SCO1, SCO2) that mediates association of MT-CO1 and MT-CO2 modules and installs heme moieties.
Metallochaperone inserts 2Cu2+ into MT-CO2
1-Cys peroxiredoxin, a bifunctional enzyme with glutathione peroxidase and phospholipase A2 activities.