COX6B1 is an 86-residue nuclear-encoded, noncatalytic structural subunit of mitochondrial cytochrome c oxidase, complex IV. It associates with the intermembrane-space face of the inner-membrane complex and supports assembly and respiratory electron transfer. Its early assembly role depends on the mitochondrial redox environment, while its presence in the mature complex supports efficient oxidase activity. The precise connection to MT-CO2 maturation remains unresolved. Pathogenic substitutions of Arg20 cause mitochondrial complex IV deficiency.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0045277 respiratory chain complex IV | IBA GO_REF:0000033 | ACCEPT | Summary: Conserved complex IV membership is supported by phylogeny and human structure. Reason: The exact human sequence occupies PTHR11387 node PTN002478571 beneath the recorded PTN000147454 ancestor. Current mouse and bovine same-term records include experimental evidence; the human target also has direct structural evidence. Target self-evidence legitimately grounds ancestral inference. Current tree/MSA inspection supports placement but does not replay the historical PAINT curation session. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:107460 SUPPORTS TRANSFER Official alias mapping: P56391. Current exact same-term records include UniProtKB:P56391!327594715 IDA PMID:34616041, UniProtKB:P56391!327594716 IDA PMID:38575788. PANTHER:PTN000147454 SUPPORTS TRANSFER Current PTHR11387 topology places the exact human target beneath this ancestor; current tree/MSA do not reconstruct the historical IBD session. UniProtKB:P00429 SUPPORTS TRANSFER Official alias mapping: P00429. Current exact same-term records include UniProtKB:P00429!357405347 IDA PMID:8638158. UniProtKB:P14854 SUPPORTS TRANSFER Official alias mapping: P14854. Current exact same-term records include UniProtKB:P14854!28807125 IPI PMID:30030519. This is legitimate target descendant evidence, not circular support. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Mitochondrial localization is conserved and independently observed in human cells. Reason: Current PTHR11387 topology places the human target below PTN000147427. Official FlyBase mapping resolves to two UniProt products; Q9VWD1 carries mitochondrial IDA, while Q8IQW2 has inferred records. Mouse, bovine and human records corroborate localization. COX6B2 supports shared organelle localization without implying interchangeable rescue activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: FB:FBgn0031066 SUPPORTS TRANSFER Official alias mapping: Q8IQW2, Q9VWD1. Current exact same-term records include UniProtKB:Q9VWD1!59240920 IDA PMID:20833144. MGI:MGI:107460 SUPPORTS TRANSFER Official alias mapping: P56391. Current exact same-term records include UniProtKB:P56391!327594701 HDA PMID:14651853, UniProtKB:P56391!327594702 HDA PMID:14651853, UniProtKB:P56391!327594703 HDA PMID:14651853, UniProtKB:P56391!327594704 HDA PMID:14651853, UniProtKB:P56391!327594705 HDA PMID:18614015. PANTHER:PTN000147427 SUPPORTS TRANSFER Current PTHR11387 topology places the exact human target beneath this ancestor; current tree/MSA do not reconstruct the historical IBD session. UniProtKB:P00429 SOURCE WEAK OR INFERRED Official aliases and complete current same-term records were inspected; available records are inferred or statement-level. UniProtKB:P14854 SUPPORTS TRANSFER Official alias mapping: P14854. Current exact same-term records include UniProtKB:P14854!28807115 IDA GO_REF:0000052, UniProtKB:P14854!28807116 HTP PMID:34800366. This is legitimate target descendant evidence, not circular support. UniProtKB:Q6YFQ2 SUPPORTS TRANSFER Official alias mapping: Q6YFQ2. Current exact same-term records include UniProtKB:Q6YFQ2!29155389 HTP PMID:34800366. |
| GO:0005743 mitochondrial inner membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The inner-membrane complex is the conserved location of COX6B1. Reason: The target lies beneath PTN000147454 in the current tree. Mouse and bovine records carry experimental inner-membrane support, and human structure places COX6B1 on the intermembrane-space face of complex IV. Peripheral association with an integral membrane complex is compatible with this location; it does not require a COX6B1 transmembrane helix. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:107460 SUPPORTS TRANSFER Official alias mapping: P56391. Current exact same-term records include UniProtKB:P56391!327594697 IDA PMID:34616041, UniProtKB:P56391!327594698 IDA PMID:38575788, UniProtKB:P56391!327594708 HDA PMID:12865426. PANTHER:PTN000147454 SUPPORTS TRANSFER Current PTHR11387 topology places the exact human target beneath this ancestor; current tree/MSA do not reconstruct the historical IBD session. UniProtKB:P00429 SUPPORTS TRANSFER Official alias mapping: P00429. Current exact same-term records include UniProtKB:P00429!357405343 EXP PMID:27605664, UniProtKB:P00429!357405344 EXP PMID:31533957. UniProtKB:P14854 SUPPORTS TRANSFER Official alias mapping: P14854. Current exact same-term records include UniProtKB:P14854!28807118 EXP PMID:30030519. This is legitimate target descendant evidence, not circular support. |
| GO:0005739 mitochondrion | IEA GO_REF:0000002 | ACCEPT | Summary: The InterPro family mappings support mitochondrial localization. Reason: Current IPR003213 and IPR036549 explicitly map to mitochondrion. Target family membership and independent human proteomics and immunofluorescence support the mapping. Other general family descriptions are not transferred into untested target activities. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR003213 SUPPORTS TRANSFER Current InterPro entry explicitly carries this GO mapping; exact target membership is present in reviewed UniProt. InterPro:IPR036549 SUPPORTS TRANSFER Current InterPro entry explicitly carries this GO mapping; exact target membership is present in reviewed UniProt. |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: The combined mapping agrees with the experimentally established membrane association. Reason: The complete current source identifies mouse P56391, its authenticated Ensembl protein ENSMUSP00000075150, and the SL-0168 inner-membrane vocabulary mapping. Current mouse same-term experimental records and human structure support the location. SL-0168 is a controlled location entry, not an experimental donor protein. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P56391 SUPPORTS TRANSFER Official alias mapping: P56391. Current exact same-term records include UniProtKB:P56391!327594697 IDA PMID:34616041, UniProtKB:P56391!327594698 IDA PMID:38575788, UniProtKB:P56391!327594708 HDA PMID:12865426. ensembl:ENSMUSP00000075150 SUPPORTS TRANSFER Official alias mapping: P56391. Current exact same-term records include UniProtKB:P56391!327594697 IDA PMID:34616041, UniProtKB:P56391!327594698 IDA PMID:38575788, UniProtKB:P56391!327594708 HDA PMID:12865426. UniProtKB-SubCell:SL-0168 SUPPORTS TRANSFER SL-0168 is the official mitochondrial-inner-membrane vocabulary mapping, not an experimental donor. |
| GO:0045277 respiratory chain complex IV | IEA GO_REF:0000120 | ACCEPT | Summary: Complex IV membership is secure despite an unresolved current ARBA branch. Reason: Current IPR003213 maps explicitly to complex IV, and authenticated mouse/Ensembl sources have same-term support. All eight current ARBA00035746 condition sets were evaluated: the target FunFam matches a branch restricted to Ascomycota, and no complete current branch matches human COX6B1. This current rule discrepancy does not overturn direct human complex membership or establish what an earlier rule version executed. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00035746 UNRESOLVED All eight current condition sets were evaluated; no complete branch matches human COX6B1. The matching FunFam branch requires Ascomycota. This is a current-rule discrepancy, not proof about an earlier execution. UniProtKB:P56391 SUPPORTS TRANSFER Official alias mapping: P56391. Current exact same-term records include UniProtKB:P56391!327594715 IDA PMID:34616041, UniProtKB:P56391!327594716 IDA PMID:38575788. ensembl:ENSMUSP00000075150 SUPPORTS TRANSFER Official alias mapping: P56391. Current exact same-term records include UniProtKB:P56391!327594715 IDA PMID:34616041, UniProtKB:P56391!327594716 IDA PMID:38575788. InterPro:IPR003213 SUPPORTS TRANSFER Current InterPro entry explicitly carries this GO mapping; exact target membership is present in reviewed UniProt. |
| GO:1902600 proton transmembrane transport | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Retain proton transport as the coupled physiological context of the assembled oxidase. Reason: The complete current GO_REF:0000108 record identifies GO:0004129 as its logical premise. COX6B1 supplies structural support to the active oxidase, whose electron-transfer reaction is coupled to proton movement. This makes participation defensible at the complex level, but the inspected human structural and knockout/rescue evidence does not resolve a COX6B1-specific contribution to proton translocation separately from assembly and oxidase activity. Selective removal of bovine VIb left proton pumping unchanged in PMID:1332762 despite increased oxidase activity. That preparation-specific result supports separating the pumping claim from the directly established structural/oxidase role; it does not establish absence of a role in every human context. Retain the coupled process as non-core and center the core on contribution to cytochrome-c oxidase activity and its specific electron-transfer step. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: GO:0004129 SUPPORTS TRANSFER The assembled oxidase activity provides a valid logical premise for this coupled process. COX6B1 contributes structural work, but a distinct subunit-specific pumping role is unresolved; the transferred process is retained as non-core. |
| GO:0006119 oxidative phosphorylation | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: Oxidative phosphorylation is a valid broader pathway context. Reason: The complete current source identifies UniPathway UPA00705. COX6B1 contributes to the terminal respiratory complex that sustains the proton gradient; it does not itself synthesize ATP. The more precise core process is electron transfer from cytochrome c to oxygen. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniPathway:UPA00705 SUPPORTS TRANSFER Current target UniProt cross-reference identifies oxidative phosphorylation; the direct vocabulary endpoint was unavailable. The pathway context agrees with complex IV biology. |
| GO:0006123 mitochondrial electron transport, cytochrome c to oxygen | NAS PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas... | ACCEPT | Summary: COX6B1 contributes structurally to cytochrome-c-to-oxygen electron transport. Reason: The human HEK293F structure identifies COX6B1 in the assembled 14-subunit enzyme. The process is performed by the complex, with its mitochondrial redox subunits carrying the cofactors; structural participation does not require COX6B1 to be an autonomous oxidoreductase. Human knockout/rescue and the low activity of AOX-bypassed incomplete complexes independently corroborate its contribution. |
| GO:0031966 mitochondrial membrane | IDA PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas... | MODIFY | Summary: Specify the mitochondrial inner membrane from the resolved human complex. Reason: PMID:30030519 purified human HEK293F respiratory supercomplexes and resolved COX6B1 on the intermembrane-space face of inner-membrane complex IV. Current GO:0005743 descends from the source mitochondrial-membrane term GO:0031966 and captures the demonstrated compartment more precisely. Peripheral association is retained without claiming a COX6B1 transmembrane helix. The separate GO:0005743 experimental annotation agrees with this refinement; each source-specific assertion retains its own identity. Proposed replacements: mitochondrial inner membrane Supporting Evidence: |
| GO:0045277 respiratory chain complex IV | IPI PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas... | ACCEPT | Summary: COX6B1 is a resolved constituent of human complex IV. Reason: The 3.3-angstrom human structure, PDB 5Z62, contains 14 distinct subunits and places COX6B1 at the intermembrane-space surface. The assayed structural complex is monomeric within a supercomplex. This is direct membership evidence and does not establish an obligatory human dimer bridge. Supporting Evidence: |
| GO:0045333 cellular respiration | NAS PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas... | KEEP AS NON CORE | Summary: Cellular respiration is a supported broader biological context. Reason: Complex IV participates in respiratory electron transport, and human COX6B1 rescue restores respiratory capacity in the knockout model. Cellular respiration encompasses additional reactions beyond this subunit; the core therefore uses the specific cytochrome-c-to-oxygen process. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Curated human immunofluorescence supports mitochondrial localization. Reason: The current HPA ICC/IF record reports supported mitochondrial localization in A-431, U-251 MG and U2OS cells. Returned experimental summaries were inspected; image pixels were not independently scored. The additional sperm principal-piece entry does not alter the mitochondrial conclusion or establish a separate core here. Supporting Evidence: GO_REF:0000052 |
| GO:0005743 mitochondrial inner membrane | EXP PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas... | ACCEPT | Summary: COX6B1 associates with the inner-membrane complex on its intermembrane side. Reason: The human structural study places COX6B1 beside the membrane-embedded oxidase subunits and the cardiolipin/NDUFA4 region. Its position is consistent with a peripheral subunit of the inner-membrane enzyme, rather than a separate soluble matrix enzyme or a membrane-spanning transporter. Supporting Evidence: |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: The original MitoCoP table directly includes the COX6B1 protein group. Reason: Authenticated Table S1 sheets A row 251 and B row 226 identify P14854/COX6B1, with MitoCoP inclusion, subtractive Class 1, spatial Cluster 1 and importomics Class 1. The subtractive mean log2 enrichment is 1.0578 and TOMM40-depletion log2 change is -2.3375. These human proteomic observations support mitochondrion. The grouped accessions and an Ambiguous membrane-association category do not establish a unique proteoform or integral topology. Supporting Evidence: |
| GO:0021762 substantia nigra development | HEP PMID:22926577 Quantitative proteomic analysis of human substantia nigra in... | MARK AS OVER ANNOTATED | Summary: Adult substantia-nigra proteomics does not establish substantia nigra development. Reason: The original study compared adult postmortem tissue from five individuals per group, aged 47–94, with disease and control groups. Table 2 detects P14854 and reports an HD/control ratio of 0.58 ± 0.05 with a PLGS downregulation metric of 0.01. GO:0021762 describes formation and maturation of the substantia nigra; the paper contains no developmental formation or maturation experiment. Preserve the true detection and disease association while rejecting that source-specific developmental inference, without asserting that COX6B1 cannot affect development. Supporting Evidence: |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-163214 | ACCEPT | Summary: The electron-transfer catalyst contains the membrane-associated COX6B1 subunit. Reason: The actual Reactome path follows event 163214 through catalyst 164322, complex 164316, COX6B1/2 set 5336172 and human entity 164299/reference 52600. This establishes the curated target location and complex context; the catalytic chemistry is attributed to the assembled enzyme. Supporting Evidence: Reactome:R-HSA-163214 |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9709406 | ACCEPT | Summary: The carbon-monoxide-binding event retains COX6B1 within its complex-IV target. Reason: Both the input complex and the CO-bound output reach the exact human COX6B1 entity through the subunit set. The inherited annotation concerns inner-membrane location. It does not imply that isolated COX6B1 binds carbon monoxide; the event describes inhibition at the oxidase heme center. Supporting Evidence: Reactome:R-HSA-9709406 |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865663 | ACCEPT | Summary: The assembly event explicitly includes the COX6B1-containing subunit set. Reason: Current event 9865663 reaches human COX6B1 through its input set and assembled output, supporting inner-membrane location during assembly. Its late-incorporation model is a curated pathway context. The published human knockout/AOX study additionally identifies an earlier redox-sensitive requirement, without demonstrating a COX6B1 copper-transfer reaction. |
| GO:0004129 cytochrome-c oxidase activity | NAS PMID:2172092 Isolation of cDNAs encoding subunit VIb of cytochrome c oxid... | ACCEPT | Summary: Retain oxidase activity at the complex-subunit contribution scope. Reason: The original NAS citation identifies the cloned human VIb subunit; its complete abstract was read, but its full paper remained unavailable after bounded recovery. Independent human structure and published knockout/rescue establish incorporation of COX6B1 into the active oxidase and restoration of respiratory capacity by complementation. This is a specific structural contribution to a defined multisubunit molecular function, rather than autonomous metal-centered catalysis. Retain that biological contribution; replacing it solely with generic structural molecule activity would discard the supported oxidase specificity. The core explicitly uses contributes_to_molecular_function, and neither the annotation nor the core is interpreted here as an assay of isolated COX6B1 catalysis. |
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Download this section (compressed HTML)Q: What molecular interaction links COX6B1 to early MT-CO2 maturation? Human redox-bypass experiments identify a dependency but do not distinguish copper transfer, redox chemistry and stabilization of an assembly intermediate.
Q: How do human Arg20His and Arg20Cys variants differ in folding, subunit stability, assembly and mature-complex contacts? Published human cell models distinguish their severity, but do not fully resolve the responsible molecular steps.
Q: How should the increased activity after selective bovine VIb removal be reconciled with deficient activity in human COX6B1-null cells? Species, detergent preparation, enzyme abundance and incomplete assembly must be separated before attributing the difference to oligomerization or cooperativity. The bovine authors proposed an active-center interaction; what direct contact or kinetic evidence could distinguish that hypothesis from changes in the enzyme preparation?
Experiment: Compare human wild-type, Arg20His and Arg20Cys complexes at matched expression and assembly abundance, combining native complex analysis, structural contacts, MT-CO2 copper occupancy and redox measurements. Include untagged rescue controls.
Hypothesis: The variants differentially alter folding and assembly contacts; a direct contribution to copper maturation remains a testable alternative.
Type: structural biology / mitochondrial biochemistry
Experiment: Measure oxidase turnover and proton pumping in preparations with verified subunit composition and oligomeric state, comparing selective VIb removal with cellular knockout-derived incomplete complexes. Control detergent, lipid and active enzyme concentrations.
Hypothesis: Preparation composition and active-complex abundance account for part of the differing bovine removal and human knockout phenotypes; obligatory dimer-dependent cooperativity is not assumed.
Type: enzyme kinetics / respirometry
Experiment: Compare patient-derived cardiomyocytes and neurons with isogenic corrected cells for complex IV abundance, respiratory capacity and assembly-intermediate composition; then measure copper occupancy where sufficient material is available.
Hypothesis: Tissue context changes the bioenergetic consequences of the established COX6B1 assembly/function defect; specific MT-CO2 hypometalation requires direct measurement.
Type: stem-cell biology / clinical model
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