COX11 is a mitochondrial inner-membrane copper metallochaperone required for assembly of cytochrome c oxidase (respiratory chain complex IV). Anchored in the inner membrane by a single N-terminal transmembrane helix, it presents a conserved C-terminal copper-binding headgroup (CFCF motif; Cys217/Cys219) on the intermembrane space side. COX11 receives Cu(I) from the soluble intermembrane-space chaperone COX17 and specifically and directly delivers/inserts copper into the CuB site of the catalytic subunit MT-CO1 (COX1) during complex IV assembly; stable copper coordination is coupled to COX11 dimerization, supported by COX19. Loss of COX11 causes mitochondrial complex IV deficiency and, in humans, an autosomal recessive infantile-onset mitochondrial encephalopathy (MC4DN23).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005743 mitochondrial inner membrane | IBA GO_REF:0000033 | ACCEPT | Summary: COX11 is a single-pass mitochondrial inner-membrane protein that functions at the inner membrane, presenting its copper-binding headgroup to the intermembrane space where it metalates MT-CO1 during complex IV assembly. This IBA localization is correct and represents the core anatomical location of the protein. Reason: Phylogenetically inferred inner-membrane localization is directly supported by experimental topology data in human and by the assembly mechanism, in which COX11 is membrane-anchored with an intermembrane-space copper-binding domain. Supporting Evidence: PMID:35750769 COX11Anchored in the inner membrane by a single transmembrane domain, mitochondrial COX11 has a C-terminal soluble headgroup located in the IMS. file:human/COX11/COX11-uniprot.txt Mitochondrion inner membrane |
| GO:0005507 copper ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: COX11 binds copper via a conserved CFCF motif (Cys217/Cys219 in human; UniProt records Cu(+) binding at residues 217 and 219). Copper ion binding is a genuine, experimentally corroborated molecular activity of this metallochaperone. This InterPro-based IEA is broader than the more specific copper chaperone activity but is correct. Reason: Copper ion binding is directly supported by the conserved copper-binding motif and by mechanistic studies showing COX11 receives and transfers Cu(I). It is a correct parent of the more informative copper chaperone activity term. Supporting Evidence: PMID:35750769 the C217 and C219 residues in the human CcO, forming the conserved copper-binding CFCF motif |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt SubCell mapping to mitochondrial inner membrane, consistent with experimental subcellular location and topology data for human COX11. Correct and concordant with the IBA and IDA inner-membrane annotations. Reason: The subcellular-location IEA agrees with experimental evidence that COX11 is a single-pass mitochondrial inner-membrane protein with its copper-binding domain on the intermembrane side. Supporting Evidence: file:human/COX11/COX11-uniprot.txt Mitochondrion inner membrane file:human/COX11/COX11-uniprot.txt Single-pass membrane protein |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: High-throughput affinity-capture/BioPlex interactome IPI (interaction with COA4/Q9NYJ1). Bare protein binding is uninformative as a molecular function and does not capture COX11's copper metallochaperone activity, though a COA4 physical association is plausible in the complex IV assembly context. Reason: protein binding is an uninformative parent MF that adds nothing beyond the specific copper chaperone activity already captured; the underlying interaction derives from a proteome-scale screen rather than a functional characterization. Supporting Evidence: PMID:33961781 cell-specific remodeling of the human interactome |
| GO:0033617 mitochondrial respiratory chain complex IV assembly | IDA PMID:35750769 Coordination of metal center biogenesis in human cytochrome ... | ACCEPT | Summary: Direct experimental evidence that COX11 is an assembly factor for complex IV that specifically and directly transfers copper to the CuB site of MT-CO1. This is a core biological process for COX11. Reason: Mechanistic study of human cytochrome c oxidase metal-center biogenesis shows COX11 acts in complex IV assembly, with a COX11 knockout retaining only ~15% fully assembled CcO. This is the central role of the gene. Supporting Evidence: PMID:35750769 COX11 and SCO1/SCO2 specifically and directly transfer Cu to the CuB and CuA sites, respectively PMID:35750769 the COX11-KO line retained 50% of COX1 and 15% of COX2 steady-state levels and 15% of residual fully assembled CcO |
| GO:0016531 copper chaperone activity | ISS GO_REF:0000024 | ACCEPT | Summary: Copper chaperone activity is the core molecular function of COX11. It receives Cu(I) from the soluble IMS chaperone COX17 and directly delivers copper to the CuB site of MT-CO1. This ISS transfer (from yeast COX11, P56940) is corroborated by direct mechanistic evidence in human cells. Reason: Copper chaperone activity captures COX11's specific molecular function better than the generic copper ion binding term and is directly supported by studies showing sequential Cu(I) transfer from COX17 to COX11 to the CuB site. Supporting Evidence: PMID:35750769 transfers Cu(I) to the IMS-exposed Cu-binding domains of IM-anchored COX11 PMID:35750769 COX11 and SCO1/SCO2 specifically and directly transfer Cu to the CuB and CuA sites, respectively |
| GO:0033617 mitochondrial respiratory chain complex IV assembly | IMP PMID:28082314 A CMC1-knockout reveals translation-independent control of h... | ACCEPT | Summary: This study of human complex IV biogenesis identifies COX11 among the CIV assembly factors relevant to COX1 metallation, supporting COX11's involvement in mitochondrial respiratory chain complex IV assembly. Concordant with the IDA annotation of the same term. Reason: Independent experimental evidence placing COX11 in the CIV assembly / COX1-metallation pathway corroborates the core complex IV assembly process; the duplicate GO term with distinct evidence is appropriate to retain. Supporting Evidence: PMID:28082314 assembly factors relevant to COX1 metallation...COX10, COX11, and SURF1 |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput identification of COX11 in the high-confidence human mitochondrial proteome. Correct but non-specific; the more precise inner-membrane localization is captured by other annotations. Reason: Mitochondrion is a correct (if broad) localization for COX11, consistent with the mitochondrial inner-membrane annotations. Retaining as a valid parent location. Supporting Evidence: PMID:34800366 high-confidence human mitochondrial proteome |
| GO:0006754 ATP biosynthetic process | IMP PMID:36030551 Biallelic pathogenic variants in COX11 are associated with a... | KEEP AS NON CORE | Summary: COX11 knockdown lowers respiration-derived (mitochondrial) ATP levels, reflecting complex IV deficiency. This is a downstream physiological consequence of impaired CIV assembly rather than a direct molecular role of COX11 in ATP biosynthesis, which is carried out by complex V. Reason: The effect on ATP levels is an indirect consequence of loss of copper delivery and CIV assembly; COX11 does not itself synthesize ATP. Retain as a non-core, phenotype-level annotation. Supporting Evidence: PMID:36030551 COX11 is required to maintain mitochondrial PMID:36030551 COX11 also participates in COX assembly by mediating copper delivery |
| GO:0030003 intracellular monoatomic cation homeostasis | IDA PMID:15840172 Physical interaction and functional coupling between ACDP4 a... | KEEP AS NON CORE | Summary: This annotation derives from the physical interaction and functional coupling between COX11 and CNNM4/ACDP4, interpreted as a role in metal-ion transport and homeostasis. COX11's copper handling is dedicated to CIV metalation rather than general cation homeostasis; this broad homeostasis term is peripheral to its core copper chaperone function. Reason: The metal-ion homeostasis inference comes from a yeast two-hybrid interaction with CNNM4 and is contextual/indirect; it does not represent COX11's core, dedicated copper-delivery role in complex IV assembly. Supporting Evidence: PMID:15840172 COX11, an implication of the role of ACDP4 in essential metal ion transport and homeostasis. |
| GO:0005515 protein binding | IPI PMID:34400285 RANBP2 mutation causing autosomal dominant acute necrotizing... | MARK AS OVER ANNOTATED | Summary: IPI for interaction with RANBP2 (P49792), reported in the context of autosomal dominant acute necrotizing encephalopathy where a RANBP2 mutation attenuates RANBP2-COX11 binding. Bare protein binding is an uninformative MF and does not represent COX11's copper metallochaperone function. Reason: protein binding is a non-informative parent term; the RANBP2 interaction is disease-context association rather than a defining molecular function of COX11. Supporting Evidence: PMID:34400285 attenuates its interaction with COX11 |
| GO:0005739 mitochondrion | IDA PMID:9878253 Identification and characterization of human cDNAs specific ... | ACCEPT | Summary: Original characterization of human COX11 cDNA reporting mitochondrial localization and subcellular topology (single-pass, intermembrane side). Correct localization, more specifically resolved to the inner membrane by other annotations. Reason: Foundational experimental evidence for mitochondrial localization of human COX11; UniProt cites this paper for the mitochondrion inner-membrane subcellular location and single-pass topology. Supporting Evidence: file:human/COX11/COX11-uniprot.txt Single-pass membrane protein file:human/COX11/COX11-uniprot.txt Intermembrane side |
| GO:0005743 mitochondrial inner membrane | IDA PMID:15229189 Human SCO1 and SCO2 have independent, cooperative functions ... | ACCEPT | Summary: Experimental subcellular-location and topology study establishing COX11 as a mitochondrial inner-membrane protein with its copper-binding domain facing the intermembrane space. This is the core anatomical location for the gene. Reason: Direct experimental localization to the mitochondrial inner membrane; UniProt cites this paper (PubMed:15229189) as the primary evidence for the inner-membrane subcellular location and matrix/IMS topology. Supporting Evidence: file:human/COX11/COX11-uniprot.txt Mitochondrion inner membrane |
| GO:0005515 protein binding | IPI PMID:15840172 Physical interaction and functional coupling between ACDP4 a... | MARK AS OVER ANNOTATED | Summary: IPI for the yeast two-hybrid interaction between COX11 and CNNM4/ACDP4 (Q6P4Q7). Bare protein binding is an uninformative molecular function and does not capture COX11's copper chaperone activity; the CNNM4 interaction is peripheral context. Reason: protein binding is a non-informative parent term; the specific copper chaperone activity already captures COX11's molecular function. The CNNM4 interaction is a Y2H association rather than a defining functional partnership. Supporting Evidence: PMID:15840172 physically interacts with COX11 and functionally coupled with this metal ion chaperone. |
| GO:0032991 protein-containing complex | IDA PMID:15840172 Physical interaction and functional coupling between ACDP4 a... | MARK AS OVER ANNOTATED | Summary: Generic protein-containing complex annotation derived from the COX11-CNNM4 co-complex detected by yeast two-hybrid / co-immunoprecipitation. This is the uninformative root complex term; the biologically meaningful complexes for COX11 are its homodimer and the complex IV assembly intermediates. Reason: GO:0032991 is an uninformative parent that conveys no specific biology. COX11 functions as a homodimer and within CIV assembly intermediates; the generic complex term does not add curation value. Supporting Evidence: PMID:15840172 physically interacts with COX11 and functionally coupled with this metal ion chaperone. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865449 | ACCEPT | Summary: Reactome-curated inner-membrane localization tied to the reaction in which the metallochaperone inserts Cu2+ into MT-CO1. Consistent with the experimental inner-membrane annotations and with COX11's copper-delivery role. Reason: TAS localization from a curated pathway reaction (Cu insertion into MT-CO1) agrees with the established mitochondrial inner-membrane localization of COX11. Supporting Evidence: file:human/COX11/COX11-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865579 | ACCEPT | Summary: Reactome-curated inner-membrane localization associated with the CIV assembly reaction in which MT-CO1 and MT-CO2 complexes associate and heme moieties are installed. Consistent with COX11's established inner-membrane localization. Reason: TAS localization from a curated complex IV assembly reaction agrees with the experimentally supported mitochondrial inner-membrane localization of COX11. Supporting Evidence: file:human/COX11/COX11-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865630 | ACCEPT | Summary: Reactome-curated inner-membrane localization tied to the reaction in which the metallochaperone inserts 2 Cu2+ into MT-CO2. Consistent with COX11's established inner-membrane localization and its role in complex IV copper delivery. Reason: TAS localization from a curated copper-insertion reaction agrees with the experimentally supported mitochondrial inner-membrane localization of COX11. Supporting Evidence: file:human/COX11/COX11-uniprot.txt Mitochondrion inner membrane |
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