COX7B

UniProt ID: P24311
Organism: Homo sapiens
Review Status: INITIALIZED
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Gene Description

COX7B (cytochrome c oxidase subunit 7B, mitochondrial; polypeptide VIIb) is a small, nuclear-encoded structural subunit of mitochondrial respiratory Complex IV (cytochrome c oxidase, COX/CIV), the terminal enzyme of the electron transport chain. Complex IV comprises a mitochondrially encoded catalytic core (MT-CO1, MT-CO2, MT-CO3) that carries out the reduction of oxygen to water, together with nuclear-encoded supernumerary subunits, of which COX7B is one. COX7B is a non-catalytic subunit that surrounds and supports the catalytic core and contributes to assembly and stability of the holoenzyme; it is a single-pass protein of the mitochondrial inner membrane (matrix-facing N-terminus, transmembrane helix, intermembrane-space C-terminus) synthesized as an 80-residue precursor with a cleaved mitochondrial transit peptide. Through its role in Complex IV it participates in mitochondrial electron transport from cytochrome c to oxygen and in oxidative phosphorylation. In humans COX7B is X-linked, and deleterious mutations cause an X-linked disorder, linear skin defects with multiple congenital anomalies (LSDMCA2), within the microphthalmia-with-linear-skin-defects (MLS/MIDAS) spectrum, an unconventional mitochondrial disease with a prominent neurodevelopmental phenotype.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005739 mitochondrion
IBA
GO_REF:0000033
ACCEPT
Summary: COX7B is a subunit of mitochondrial Complex IV and localizes to the mitochondrion. This phylogenetic (IBA) mitochondrial annotation is correct but general; the precise location is the mitochondrial inner membrane (GO:0005743).
Reason: Correct localization to the mitochondrion, consistent with COX7B being a cytochrome c oxidase subunit of the inner membrane. Retained as a correct but non-core (broad) cellular component; the specific inner-membrane term captures the core localization.
Supporting Evidence:
PMID:8382530
Isolation of a cDNA specifying subunit VIIb of human cytochrome c oxidase.
GO:0045277 respiratory chain complex IV
IBA
GO_REF:0000033
ACCEPT
Summary: COX7B is a constitutive structural subunit of respiratory chain complex IV (cytochrome c oxidase). This phylogenetic annotation captures the core cellular component/complex membership of the gene.
Reason: Complex IV membership is the defining property of COX7B, supported by structural and biochemical evidence that it is one of the 11 nuclear-encoded supernumerary subunits of the 14-subunit human cytochrome c oxidase. GO:0045277 is the current, non-obsolete term for this complex.
Supporting Evidence:
PMID:30030519
the intact monomeric complex-IV contains 14 subunits
file:human/COX7B/COX7B-uniprot.txt
COX7A2 (or COX7A1), COX7B, COX7C, COX8A and COXFA4, which are encoded
GO:0005743 mitochondrial inner membrane
IEA
GO_REF:0000044
ACCEPT
Summary: COX7B is a single-pass protein of the mitochondrial inner membrane, where Complex IV resides. This UniProt subcellular-location mapping is accurate and represents the core cellular component.
Reason: The inner mitochondrial membrane is the precise, experimentally supported localization of COX7B and of the whole cytochrome c oxidase complex.
Supporting Evidence:
file:human/COX7B/COX7B-uniprot.txt
Single-pass membrane protein
PMID:30030519
CIV is the terminal oxidase of the electron transport chain in mitochondria
GO:0006123 mitochondrial electron transport, cytochrome c to oxygen
IEA
GO_REF:0000002
ACCEPT
Summary: As a subunit of Complex IV, COX7B participates in mitochondrial electron transport from cytochrome c to oxygen. This InterPro2GO mapping (from the COX7B/VIIb family signature) assigns the correct core biological process.
Reason: GO:0006123 is the process carried out by the complex to which COX7B belongs and is the appropriate core BP for this structural subunit.
Supporting Evidence:
PMID:30030519
It accepts electrons from cytochrome c to reduce the oxygen to water
GO:0016020 membrane
IEA
GO_REF:0000117
MARK AS OVER ANNOTATED
Summary: This ARBA machine-learning annotation places COX7B in the generic 'membrane' component. It is not wrong (COX7B is an integral membrane protein) but is far more general than the well-supported mitochondrial inner membrane term.
Reason: The generic 'membrane' term is uninformative given the precise, experimentally supported mitochondrial inner membrane localization (GO:0005743). Retained but flagged as over-general.
Supporting Evidence:
file:human/COX7B/COX7B-uniprot.txt
Single-pass membrane protein
GO:1902600 proton transmembrane transport
IEA
GO_REF:0000108
KEEP AS NON CORE
Summary: This annotation is inferred by an inter-ontology logical link from the cytochrome-c oxidase activity of Complex IV (the complex pumps protons across the inner membrane). Proton pumping is a property of the mtDNA-encoded catalytic core; COX7B is a non-catalytic structural subunit that does not itself translocate protons.
Reason: Complex IV does contribute to proton transmembrane transport, so the annotation is not incorrect at the complex level, but for the individual non-catalytic COX7B subunit this is a peripheral, complex-level property rather than a core function.
Supporting Evidence:
PMID:30030519
pumps two protons from the matrix side to the intermembrane space
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome.
MARK AS OVER ANNOTATED
Summary: A single high-throughput binary (yeast two-hybrid) interaction with GNMT (Q14749) reported in the HuRI human interactome map. Bare 'protein binding' provides no informative molecular function, and this cytosolic-methyltransferase partner has no clear relationship to an inner-membrane Complex IV subunit.
Reason: Uninformative 'protein binding' from a single large-scale Y2H screen; it does not capture COX7B's actual molecular function (structural subunit of Complex IV). Retained (not removed) per policy on high-throughput IPI protein-binding annotations, but flagged as over-annotation.
Supporting Evidence:
PMID:32296183
reference interactome map of human binary protein interactions, or 'HuRI'
GO:0006119 oxidative phosphorylation
IEA
GO_REF:0000041
ACCEPT
Summary: Complex IV, and hence COX7B, participates in oxidative phosphorylation by contributing to the electron transport chain that builds the proton-motive force driving ATP synthase. This UniPathway-based mapping is correct but broader than the specific electron-transport process.
Reason: Correct higher-level biological process for a Complex IV subunit; kept as a correct, non-core (broader) BP relative to GO:0006123.
Supporting Evidence:
file:human/COX7B/COX7B-uniprot.txt
Energy metabolism; oxidative phosphorylation
file:human/COX7B/COX7B-uniprot.txt
electrochemical gradient over the inner membrane
GO:0006123 mitochondrial electron transport, cytochrome c to oxygen
NAS
PMID:30030519
Structure of the intact 14-subunit human cytochrome c oxidas...
ACCEPT
Summary: ComplexPortal (CPX-6123) NAS annotation of the core electron-transport process for a Complex IV subunit, based on the intact 14-subunit human cytochrome c oxidase structure. Duplicates the InterPro IEA assignment of the same core BP.
Reason: Correct core biological process for COX7B as a Complex IV subunit; consistent with the structural characterization of the complex.
Supporting Evidence:
PMID:30030519
It accepts electrons from cytochrome c to reduce the oxygen to water
GO:0031966 mitochondrial membrane
IDA
PMID:30030519
Structure of the intact 14-subunit human cytochrome c oxidas...
ACCEPT
Summary: ComplexPortal IDA localization to the mitochondrial membrane, from the cryo-EM structure of human Complex IV. Correct, though broader than the mitochondrial inner membrane term that specifies COX7B's exact location.
Reason: Accurate mitochondrial-membrane localization supported by structural data; retained as a correct but non-core (broader) cellular component relative to GO:0005743.
Supporting Evidence:
PMID:30030519
CIV is the terminal oxidase of the electron transport chain in mitochondria
GO:0045277 respiratory chain complex IV
IPI
PMID:30030519
Structure of the intact 14-subunit human cytochrome c oxidas...
ACCEPT
Summary: ComplexPortal IPI membership of respiratory chain complex IV, established by the intact 14-subunit human cytochrome c oxidase structure in which COX7B is resolved as a subunit. This is the core complex membership for COX7B.
Reason: Directly supported structural evidence that COX7B is part of complex IV; GO:0045277 is the current term for the complex.
Supporting Evidence:
PMID:30030519
the intact monomeric complex-IV contains 14 subunits
GO:0045333 cellular respiration
NAS
PMID:30030519
Structure of the intact 14-subunit human cytochrome c oxidas...
ACCEPT
Summary: ComplexPortal NAS annotation to cellular respiration, the broad process encompassing the electron transport chain and oxidative phosphorylation to which Complex IV contributes.
Reason: Correct high-level biological process for a Complex IV subunit; retained as a correct, non-core (broad) BP relative to the specific cytochrome-c-to-oxygen electron transport term.
Supporting Evidence:
PMID:30030519
CIV is the terminal oxidase of the electron transport chain in mitochondria
GO:0005743 mitochondrial inner membrane
EXP
PMID:30030519
Structure of the intact 14-subunit human cytochrome c oxidas...
ACCEPT
Summary: Experimental (structural) localization of COX7B to the mitochondrial inner membrane, consistent with UniProt topology (matrix-facing N-terminus, single transmembrane helix, intermembrane-space C-terminus). This is the core cellular component.
Reason: The mitochondrial inner membrane is the precise, experimentally supported localization of COX7B within Complex IV.
Supporting Evidence:
file:human/COX7B/COX7B-uniprot.txt
Single-pass membrane protein
GO:0005739 mitochondrion
HTP
PMID:34800366
Quantitative high-confidence human mitochondrial proteome an...
ACCEPT
Summary: High-throughput detection of COX7B in the high-confidence human mitochondrial proteome. Correct mitochondrial localization, though general relative to the inner-membrane term.
Reason: Supports mitochondrial localization of COX7B; retained as a correct but non-core (broad) cellular component.
Supporting Evidence:
PMID:34800366
human mitochondrial proteome
GO:0005743 mitochondrial inner membrane
TAS
Reactome:R-HSA-163214
ACCEPT
Summary: Reactome traceable-author-statement localization of COX7B to the mitochondrial inner membrane in the context of electron transfer from reduced cytochrome c to molecular oxygen. Consistent with the core localization.
Reason: Correct inner-membrane localization from a curated pathway resource; consistent with experimental and structural evidence.
Supporting Evidence:
file:human/COX7B/COX7B-uniprot.txt
Single-pass membrane protein
GO:0005743 mitochondrial inner membrane
TAS
Reactome:R-HSA-9709406
ACCEPT
Summary: Reactome TAS localization of COX7B to the mitochondrial inner membrane (in the CO-binding-to-cytochrome-c-oxidase reaction context). Consistent with the core localization.
Reason: Correct inner-membrane localization from a curated pathway resource.
Supporting Evidence:
file:human/COX7B/COX7B-uniprot.txt
Single-pass membrane protein
GO:0005743 mitochondrial inner membrane
TAS
Reactome:R-HSA-9865579
ACCEPT
Summary: Reactome TAS localization of COX7B to the mitochondrial inner membrane (Complex IV assembly context, MT-CO1/MT-CO2 heme installation). Consistent with the core localization.
Reason: Correct inner-membrane localization from a curated pathway resource.
Supporting Evidence:
file:human/COX7B/COX7B-uniprot.txt
Single-pass membrane protein
GO:0005743 mitochondrial inner membrane
TAS
Reactome:R-HSA-9865663
ACCEPT
Summary: Reactome TAS localization of COX7B to the mitochondrial inner membrane (Complex IV assembly context in which COX7B binds the holo-MT-CO1,2 complex). Consistent with the core localization.
Reason: Correct inner-membrane localization from a curated pathway resource; the assembly context is consistent with COX7B being a supernumerary subunit added during Complex IV biogenesis.
Supporting Evidence:
file:human/COX7B/COX7B-uniprot.txt
Single-pass membrane protein
GO:0007417 central nervous system development
IMP
PMID:23122588
Mutations in COX7B cause microphthalmia with linear skin les...
KEEP AS NON CORE
Summary: COX7B knockdown in medaka recapitulates the microphthalmia-with-linear-skin-lesions (MLS) phenotype with microcephaly and microphthalmia, demonstrating that Complex IV activity is required for vertebrate CNS development. This is a downstream developmental consequence of loss of cytochrome c oxidase activity rather than a distinct molecular role of COX7B.
Reason: The developmental/neurodevelopmental phenotype is a genuine, experimentally supported organismal consequence of COX7B loss-of-function (its disease mechanism), but it reflects the general requirement for Complex IV activity in energy metabolism, not a core molecular function of this structural subunit. Retained as an important non-core annotation.
Supporting Evidence:
PMID:23122588
essential function of complex IV activity in vertebrate CNS development
PMID:23122588
COX7B encodes a poorly characterized structural subunit of cytochrome c oxidase
GO:0004129 cytochrome-c oxidase activity
TAS
PMID:8382530
Isolation of a cDNA specifying subunit VIIb of human cytochr...
MODIFY
Summary: This legacy TAS annotation assigns the whole-complex catalytic cytochrome-c oxidase activity to COX7B. COX7B is a non-catalytic supernumerary subunit; the oxygen-reduction chemistry is performed by the mtDNA-encoded catalytic core (MT-CO1, MT-CO2). The cited paper reports the cDNA of the nuclear-encoded structural subunit VIIb, not that COX7B itself catalyzes the reaction.
Reason: COX7B does not itself enable cytochrome-c oxidase catalysis; its molecular function is structural, contributing to the integrity and assembly of the complex that performs catalysis. Replace the catalytic MF with structural molecule activity (GO:0005198). The catalytic activity is retained at the complex level via contributes_to in core_functions.
Proposed replacements: structural molecule activity
Supporting Evidence:
PMID:8382530
the last remaining uncharacterized nuclear-encoded
PMID:23122588
COX7B encodes a poorly characterized structural subunit of cytochrome c oxidase

Core Functions

Structural (non-catalytic) subunit of mitochondrial respiratory Complex IV (cytochrome c oxidase) that contributes to assembly and stability of the holoenzyme, supporting electron transport from cytochrome c to oxygen in the mitochondrial inner membrane.

Supporting Evidence:
  • PMID:23122588
    COX7B encodes a poorly characterized structural subunit of cytochrome c oxidase
  • PMID:30030519
    the intact monomeric complex-IV contains 14 subunits

References

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Notes

(COX7B-notes.md)

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