id: P22695
gene_symbol: UQCRC2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  UQCRC2 (Cytochrome b-c1 complex subunit 2, mitochondrial; core protein II; QCR2;
  ubiquinol-cytochrome-c reductase complex core protein 2) is one of the two large
  "core" subunits (with UQCRC1/core protein 1) of mitochondrial respiratory Complex
  III, the cytochrome bc1 / ubiquinol-cytochrome c reductase of the electron
  transport chain. Complex III is an eleven-subunit, obligate-dimeric enzyme of the
  inner mitochondrial membrane that transfers electrons from ubiquinol to cytochrome
  c and couples this redox chemistry to proton translocation across the inner
  membrane via the protonmotive Q cycle; the catalytic redox centres reside in
  cytochrome b, the Rieske iron-sulfur protein UQCRFS1, and cytochrome c1, not in
  the core proteins. UQCRC2 is a non-catalytic structural subunit required for
  assembly and stability of the complex; it is a peripheral inner-membrane protein
  exposed to the matrix side. The two core proteins are homologous to the alpha/beta
  subunits of the mitochondrial-processing peptidase and retain the peptidase M16
  fold, but human UQCRC2 lacks the catalytic zinc-binding motif and any peptidase
  activity is unproven (it has been proposed only as a possible participant in
  in situ processing of the UQCRFS1 Rieske precursor). Complex III assembles with
  Complexes I and IV into supercomplexes/respirasomes. Biallelic UQCRC2 loss-of-
  function variants cause mitochondrial complex III deficiency, nuclear type 5
  (MC3DN5), a metabolic/neurological disorder with neonatal-onset recurrent
  metabolic decompensation, encephalopathy, lactic acidosis, and hepato-renal
  involvement.
existing_annotations:
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (PAN-GO/GO_Central) inference that UQCRC2 acts in the
      mitochondrion. Correct but general; the informative locations are the inner
      membrane and respiratory chain complex III.
    action: ACCEPT
    reason: >-
      UQCRC2 is an established mitochondrial protein, a subunit of inner-membrane
      Complex III. The term is accurate though non-specific; retained as a
      correct high-level localization.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0045275
    label: respiratory chain complex III
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      Phylogenetic inference that UQCRC2 is part of respiratory chain complex III.
      This is a core, correct annotation: UQCRC2 (core protein 2) is one of the
      eleven subunits of the cytochrome bc1 complex.
    action: ACCEPT
    reason: >-
      Well supported across orthologs and by structure; UQCRC2 is a constitutive
      structural subunit of Complex III. This is one of the two most informative
      annotations for the gene.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: >-
        Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1
        complex, complex III, CIII), a multisubunit enzyme composed of 11 subunits
- term:
    id: GO:0004222
    label: metalloendopeptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro (peptidase M16 family, IPR001431) electronically maps
      metalloendopeptidase activity. UQCRC2 retains the M16/MPP-like fold but is a
      non-catalytic core subunit: it lacks the canonical M16 inverted zinc-binding
      motif (HXXEH), and no peptidase activity has been demonstrated for human
      UQCRC2. UniProt only hedges that the core proteins "seem to have preserved"
      MPP properties (By similarity) and that UQCRC2 "May be involved" in UQCRFS1
      processing (Probable).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Fold-based electronic over-annotation. A sequence scan finds no HXXEH
      catalytic motif in mature UQCRC2, and Reactome lists UQCRC1/UQCRC2 only as
      possible (not demonstrated) candidates for the UQCRFS1-processing peptidase.
      PAN-GO/GO_Central assigns no catalytic MF. The activity is not part of the
      verified core function (structural subunit of Complex III), so it should not
      be treated as a real molecular function.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: Belongs to the peptidase M16 family. UQCRC2/QCR2 subfamily.
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: >-
        May be involved in the in situ processing of UQCRFS1 into the mature Rieske
        protein and its mitochondrial targeting sequence (MTS)/subunit 9 when
        incorporated into complex III
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: >-
      ARBA machine-learning electronic annotation to mitochondrion. Consistent
      with the well-established mitochondrial localization of UQCRC2.
    action: ACCEPT
    reason: >-
      Correct, though general; the more specific inner-membrane / Complex III terms
      are the informative ones.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Combined-IEA electronic annotation (with mouse ortholog Q9DB77 and
      UniProt-SubCell) to mitochondrial inner membrane. Matches the curated
      subcellular location of UQCRC2 as a peripheral inner-membrane subunit of
      Complex III on the matrix side.
    action: ACCEPT
    reason: >-
      Accurate and specific; this is a core, informative localization for UQCRC2.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro (peptidase M16) electronic mapping to proteolysis. This is the
      biological-process counterpart of the metalloendopeptidase MF IEA and rests
      on the same unproven premise that UQCRC2 is catalytically active.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Human UQCRC2 is a non-catalytic core subunit that has lost the M16 catalytic
      zinc-binding motif; no proteolytic activity is demonstrated. Any involvement
      in UQCRFS1 maturation is speculative (only "Probable" in UniProt; Reactome
      lists UQCRC1/UQCRC2 only as possible candidates). This is a fold-derived
      over-annotation, not the gene's core process.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: >-
        May be involved in the in situ processing of UQCRFS1 into the mature Rieske
        protein and its mitochondrial targeting sequence (MTS)/subunit 9 when
        incorporated into complex III
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro (IPR011249, Metalloenzyme LuxS/M16) electronic mapping to metal ion
      binding, reflecting the predicted zinc-binding of the M16 peptidase fold.
      As with the peptidase MF, the catalytic/metal-binding site is degenerate in
      human UQCRC2.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The metal-binding annotation is a by-product of the M16 fold prediction; the
      catalytic zinc-binding motif (HXXEH) is absent and no metal cofactor has been
      shown for UQCRC2. Not a verified molecular function.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: Belongs to the peptidase M16 family. UQCRC2/QCR2 subfamily.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21078624
  qualifier: enables
  review:
    summary: >-
      IntAct IPI from an expanded ataxia-interactome study, recording a binary
      interaction (with CACNA1A, O00555). The GO term protein binding is
      uninformative and this is a high-throughput interactome hit unrelated to the
      established Complex III function of UQCRC2.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding conveys no specific molecular function; per curation
      guidelines it should not be treated as a core function. The interaction is
      from a large-scale interactome screen and is not shown to be physiologically
      relevant to UQCRC2's role as a Complex III subunit.
    supported_by:
    - reference_id: PMID:21078624
      supporting_text: >-
        Comparison of an expanded ataxia interactome with patient medical records
        reveals a relationship between macular degeneration and ataxia.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: >-
      IntAct IPI from a neurodegenerative-disease interactome map (Y2H/network),
      recording binary interactions (e.g. SNW1, DLG-family). Uninformative
      protein-binding term from a large-scale screen.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding is uninformative and these are high-throughput
      interactome interactions of unclear relevance to UQCRC2's Complex III
      function. Kept (not removed) as a valid but non-core interaction record.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: >-
        Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
        and Uncovers Widespread Protein Aggregation in Affected Brains.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36115835
  qualifier: enables
  review:
    summary: >-
      IntAct IPI from a fragmentomics affinity-mapping study; the partners are
      predominantly PDZ-domain proteins (DLG1-4, MAGI1/2, SCRIB, PATJ, GRIP1/2,
      etc.), consistent with an affinity screen of PDZ-binding motifs rather than
      an in vivo mitochondrial interaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding is uninformative; this cluster of PDZ-domain
      interactors reflects the assay design and is not evidence for a Complex III
      related molecular function. Retained as a non-core interaction record.
    supported_by:
    - reference_id: PMID:36115835
      supporting_text: Quantitative fragmentomics allow affinity mapping of interactomes.
- term:
    id: GO:0045275
    label: respiratory chain complex III
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: >-
      Combined-IEA electronic annotation (with mouse ortholog) placing UQCRC2 in
      respiratory chain complex III. Duplicates the IBA/IDA CIII annotations and is
      correct.
    action: ACCEPT
    reason: >-
      UQCRC2 is a constitutive structural subunit of Complex III; this is a core,
      correct annotation.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: >-
        Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1
        complex, complex III, CIII), a multisubunit enzyme composed of 11 subunits
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Human Protein Atlas immunofluorescence (IDA) localizing UQCRC2 to the
      mitochondrion. Consistent with all other evidence.
    action: ACCEPT
    reason: >-
      Direct localization evidence; correct though general relative to the
      inner-membrane/CIII terms.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ISS transfer from the yeast ortholog QCR2 (P07257) assigning mitochondrial
      inner membrane. Matches the curated location of human UQCRC2.
    action: ACCEPT
    reason: >-
      Accurate, specific, core localization; consistent with experimental and
      electronic evidence.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:28844695
  qualifier: located_in
  review:
    summary: >-
      ComplexPortal IDA based on the cryo-EM structure of the human respiratory
      megacomplex I2III2IV2, in which UQCRC2 is resolved as an inner-membrane
      Complex III subunit.
    action: ACCEPT
    reason: >-
      Direct structural evidence for inner-membrane localization within Complex
      III; a core, well-supported CC annotation.
    supported_by:
    - reference_id: PMID:28844695
      supporting_text: >-
        Architecture of Human Mitochondrial Respiratory Megacomplex I(2)III(2)IV(2).
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0006122
    label: mitochondrial electron transport, ubiquinol to cytochrome c
  evidence_type: NAS
  original_reference_id: PMID:28844695
  qualifier: involved_in
  review:
    summary: >-
      ComplexPortal NAS annotation of UQCRC2 to the core Complex III process:
      mitochondrial electron transport from ubiquinol to cytochrome c. As a
      required structural subunit of CIII, UQCRC2 is a bona fide participant in
      this process.
    action: ACCEPT
    reason: >-
      This is the central biological process performed by Complex III, of which
      UQCRC2 is an obligate subunit. Although UQCRC2 itself is non-catalytic, the
      inner-membrane electron-transfer / proton-pumping activity requires the
      assembled complex including the core proteins. This is the most specific and
      informative BP for the gene.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: >-
        The cytochrome b-c1 complex catalyzes electron transfer from ubiquinol to
        cytochrome c, linking this redox reaction to translocation of protons across
        the mitochondrial inner membrane
- term:
    id: GO:0045275
    label: respiratory chain complex III
  evidence_type: IPI
  original_reference_id: PMID:28844695
  qualifier: part_of
  review:
    summary: >-
      ComplexPortal IPI placing UQCRC2 in respiratory chain complex III, based on
      the cryo-EM megacomplex structure. Core, correct complex-membership
      annotation.
    action: ACCEPT
    reason: >-
      Structural evidence that UQCRC2 is a subunit of Complex III; one of the two
      most informative annotations for this gene.
    supported_by:
    - reference_id: PMID:28844695
      supporting_text: >-
        Architecture of Human Mitochondrial Respiratory Megacomplex I(2)III(2)IV(2).
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: >-
        Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1
        complex, complex III, CIII), a multisubunit enzyme composed of 11 subunits
- term:
    id: GO:0045333
    label: cellular respiration
  evidence_type: NAS
  original_reference_id: PMID:28844695
  qualifier: involved_in
  review:
    summary: >-
      ComplexPortal NAS annotation to cellular respiration, the broad process
      encompassing Complex III electron transport. Accurate but more general than
      GO:0006122.
    action: ACCEPT
    reason: >-
      Correct high-level process for a Complex III subunit; retained as accurate
      but kept non-core relative to the specific ubiquinol-to-cytochrome-c term.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: >-
        part of the mitochondrial electron transport chain which drives oxidative
        phosphorylation
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput annotation to mitochondrion from a quantitative
      high-confidence human mitochondrial proteome study. Confirms mitochondrial
      localization.
    action: ACCEPT
    reason: >-
      Supported by high-confidence mitochondrial proteomics; correct though
      general.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: >-
        Quantitative high-confidence human mitochondrial proteome and its dynamics
        in cellular context.
- term:
    id: GO:0045275
    label: respiratory chain complex III
  evidence_type: IDA
  original_reference_id: PMID:23168492
  qualifier: part_of
  review:
    summary: >-
      IDA (UniProt) of Complex III membership from a study of CIII assembly
      (LYRM7/MZM1L as UQCRFS1 chaperone), in which UQCRC2 features as a structural
      subunit of the mature/assembling complex.
    action: ACCEPT
    reason: >-
      Consistent with all evidence that UQCRC2 is part of Complex III; core,
      correct annotation. Cached record is abstract-only and the paper is by the
      CIII-assembly group; defer to the experimental curator.
    supported_by:
    - reference_id: PMID:23168492
      supporting_text: >-
        LYRM7/MZM1L is a UQCRFS1 chaperone involved in the last steps of
        mitochondrial Complex III assembly in human cells.
- term:
    id: GO:0045275
    label: respiratory chain complex III
  evidence_type: IDA
  original_reference_id: PMID:31536960
  qualifier: part_of
  review:
    summary: >-
      IDA (UniProt) of Complex III membership from a mitochondrial-interactome /
      co-fractionation study of neuronal reprogramming, which also reports the
      UQCRC2-RAB5IF interaction. UQCRC2 co-fractionates as a Complex III subunit.
    action: ACCEPT
    reason: >-
      Core, correct complex-membership annotation; consistent with structural and
      phylogenetic evidence.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: Interacts with RAB5IF
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35101990
  qualifier: enables
  review:
    summary: >-
      IPI (UniProt) recording interaction with mitolamban/STMP1 (P0DP99). The
      mitolamban paper shows this cardiac inner-membrane microprotein
      co-immunoprecipitates and co-migrates with Complex III subunits (UQCRC1,
      UQCRC2, UQCR10) and regulates CIII assembly/activity. Biologically plausible
      and CIII-relevant, but the GO term protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Although this interaction is more physiologically relevant than the generic
      interactome hits (mitolamban is a CIII-assembly regulator), the bare
      protein binding term does not describe a specific molecular function and is
      not itself a core function of UQCRC2. Kept as a non-core interaction record
      rather than removed.
    supported_by:
    - reference_id: PMID:35101990
      supporting_text: >-
        The four most-enriched proteins in the Mtlbn IP sample were all components
        of complex III of the mitochondrial respiratory chain (UQCRC1, UQCRC2,
        UQCR10, and UQCRFS1P1)
    - reference_id: PMID:35101990
      supporting_text: UQCRC1, UQCRC2, and UQCR10 was confirmed
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31536960
  qualifier: enables
  review:
    summary: >-
      IPI (UniProt) recording the UQCRC2-RAB5IF (Q9BUV8) interaction from the
      mitochondrial-interactome study. UniProt curates this as a documented
      interaction of UQCRC2, but the GO term protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding conveys no specific function. The RAB5IF interaction is
      a curated binary interaction but does not by itself define a molecular
      function; retained as a non-core interaction record.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: Interacts with RAB5IF
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:20833797
  qualifier: located_in
  review:
    summary: >-
      High-throughput direct-assay (HDA) mitochondrion localization from a
      phosphoproteome study of functional mitochondria isolated from human muscle,
      in which UQCRC2 was identified among inner-membrane respiratory complex
      subunits.
    action: ACCEPT
    reason: >-
      Supported by mitochondrial proteomics; correct though general.
    supported_by:
    - reference_id: PMID:20833797
      supporting_text: >-
        phosphorylation of inner membrane protein complexes
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-164651
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS for inner-membrane localization, tied to the reaction for
      electron transfer from ubiquinol to cytochrome c of complex III (the Q cycle).
      Consistent with UQCRC2 as an inner-membrane CIII subunit.
    action: ACCEPT
    reason: >-
      Authoritative traceable statement; core, correct localization.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9837978
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS (inner membrane) associated with a reaction in which LONP1 binds
      mitochondrial inner membrane proteins; a protein-quality-control reaction in
      which UQCRC2, as an inner-membrane protein, is a participant. The
      localization term itself is correct.
    action: ACCEPT
    reason: >-
      Correct inner-membrane localization; consistent with all other evidence.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838004
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS (inner membrane) associated with a reaction in which LONP1
      degrades mitochondrial inner membrane proteins. The inner-membrane
      localization is correct.
    action: ACCEPT
    reason: >-
      Correct localization; retained.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9906017
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS (inner membrane) associated with a CIII-maturation reaction in
      which an unknown peptidase cleaves the UQCRFS1 subunit and UQCRC1/UQCRC2 are
      noted only as possible candidate peptidases. The localization term is correct.
    action: ACCEPT
    reason: >-
      Inner-membrane localization is correct. (The associated speculative peptidase
      role is addressed under the InterPro metalloendopeptidase/proteolysis IEAs,
      which are marked as over-annotations.)
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9906042
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS (inner membrane) associated with a reaction in which TTC19
      clears UQCRFS1 fragments from Complex III. Correct inner-membrane
      localization for UQCRC2.
    action: ACCEPT
    reason: >-
      Correct localization; retained.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: PMID:8288258
  qualifier: located_in
  review:
    summary: >-
      TAS (ProtInc/PINC) inner-membrane localization from the paper assigning the
      UQCRC2 gene (core protein II of the cytochrome bc1 complex) to human
      chromosome 16p12. Correct localization for a CIII inner-membrane subunit.
    action: ACCEPT
    reason: >-
      Correct, core localization consistent with all other evidence.
    supported_by:
    - reference_id: PMID:8288258
      supporting_text: >-
        Assignment of the gene for the core protein II (UQCRC2) subunit of the
        mitochondrial cytochrome bc1 complex to human chromosome 16p12.
- term:
    id: GO:0006119
    label: oxidative phosphorylation
  evidence_type: TAS
  original_reference_id: PMID:8288258
  qualifier: involved_in
  review:
    summary: >-
      TAS annotation to oxidative phosphorylation. Complex III is an integral part
      of the OXPHOS electron transport chain, so a CIII subunit is legitimately
      involved in oxidative phosphorylation. More general than the specific
      ubiquinol-to-cytochrome-c term.
    action: ACCEPT
    reason: >-
      Accurate high-level process for a Complex III subunit; retained as correct
      but non-core relative to GO:0006122.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: >-
        part of the mitochondrial electron transport chain which drives oxidative
        phosphorylation
- term:
    id: GO:0009060
    label: aerobic respiration
  evidence_type: TAS
  original_reference_id: PMID:8288258
  qualifier: involved_in
  review:
    summary: >-
      TAS annotation to aerobic respiration. As a subunit of Complex III of the
      aerobic electron transport chain (which passes electrons ultimately to
      molecular oxygen via CIV), UQCRC2 participates in aerobic respiration.
      Accurate but general.
    action: ACCEPT
    reason: >-
      Correct high-level respiratory process for a CIII subunit; retained as
      accurate but non-core relative to the specific electron-transport term.
    supported_by:
    - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
      supporting_text: >-
        cooperate to transfer electrons derived from NADH and succinate to
        molecular oxygen
core_functions:
- description: >-
    UQCRC2 (core protein 2) is a non-catalytic structural subunit of mitochondrial
    respiratory Complex III (cytochrome bc1 / ubiquinol-cytochrome c reductase) in
    the inner mitochondrial membrane, required for assembly and stability of the
    complex. The assembled complex transfers electrons from ubiquinol to cytochrome
    c and couples this to proton translocation (the Q cycle) during aerobic
    respiration / oxidative phosphorylation. UQCRC2 has no independent catalytic
    activity (no verifiable structural-molecule or peptidase MF term is carried in
    GOA; the InterPro-derived peptidase/metal-binding MF/BP annotations are
    fold-based over-annotations), so its core function is captured by its Complex III
    membership, inner-membrane location, and participation in ubiquinol-to-cytochrome
    c electron transport.
  supported_by:
  - reference_id: PMID:28844695
    supporting_text: >-
      Architecture of Human Mitochondrial Respiratory Megacomplex I(2)III(2)IV(2).
  - reference_id: file:human/UQCRC2/UQCRC2-uniprot.txt
    supporting_text: >-
      The cytochrome b-c1 complex catalyzes electron transfer from ubiquinol to
      cytochrome c, linking this redox reaction to translocation of protons across
      the mitochondrial inner membrane
  directly_involved_in:
  - id: GO:0006122
    label: mitochondrial electron transport, ubiquinol to cytochrome c
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  in_complex:
    id: GO:0045275
    label: respiratory chain complex III
suggested_questions:
- question: >-
    Does human UQCRC2 retain any residual peptidase activity toward the UQCRFS1
    Rieske precursor during Complex III assembly, or is UQCRFS1 processing entirely
    dependent on other peptidases?
- question: >-
    Are any of the reported PDZ-domain / interactome interactions of UQCRC2
    (e.g. DLG family, MAGI, SCRIB) physiologically relevant, or artifacts of the
    affinity/network assays?
suggested_experiments:
- description: >-
    Reconstitute Complex III assembly in cells expressing catalytic-site (M16 motif)
    UQCRC2 variants to test whether any residual metallopeptidase capacity
    contributes to UQCRFS1 maturation.
- description: >-
    Structurally and biochemically define the UQCRC2-mitolamban (STMP1) and
    UQCRC2-RAB5IF interactions within assembling Complex III to clarify their roles
    in CIII biogenesis and supercomplex formation.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/UQCRC2/UQCRC2-uniprot.txt
  title: UniProtKB entry P22695 (QCR2_HUMAN), Cytochrome b-c1 complex subunit 2, mitochondrial
  findings: []
- id: PMID:20833797
  title: Phosphoproteome analysis of functional mitochondria isolated from resting
    human muscle reveals extensive phosphorylation of inner membrane protein complexes
    and enzymes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Phosphoproteome study of human muscle mitochondria; supports mitochondrial /
      inner-membrane localization of UQCRC2 but not a specific function.
- id: PMID:21078624
  title: Comparison of an expanded ataxia interactome with patient medical records
    reveals a relationship between macular degeneration and ataxia.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Source of a bare protein-binding IPI (CACNA1A); large-scale interactome, not
      informative for UQCRC2's Complex III function.
- id: PMID:23168492
  title: LYRM7/MZM1L is a UQCRFS1 chaperone involved in the last steps of mitochondrial
    Complex III assembly in human cells.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Study of human Complex III assembly (UQCRFS1 insertion) in which UQCRC2 is a
      structural subunit; supports the CIII part_of annotation.
- id: PMID:28844695
  title: Architecture of Human Mitochondrial Respiratory Megacomplex I(2)III(2)IV(2).
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Cryo-EM structure of the human respiratory megacomplex; directly places
      UQCRC2 as an inner-membrane subunit of Complex III. Primary structural
      support for the core CC/BP annotations.
- id: PMID:31536960
  title: Rewiring of the Human Mitochondrial Interactome during Neuronal Reprogramming
    Reveals Regulators of the Respirasome and Neurogenesis.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Mitochondrial co-fractionation/interactome study supporting UQCRC2 as a
      Complex III subunit and its interaction with RAB5IF.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale neurodegeneration interactome; source of bare protein-binding
      IPIs of unclear relevance to UQCRC2 function.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-confidence mitochondrial proteome; supports mitochondrial localization
      of UQCRC2.
- id: PMID:35101990
  title: The cardiac-enriched microprotein mitolamban regulates mitochondrial respiratory
    complex assembly and function in mice.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Mitolamban (STMP1) co-IPs and co-migrates with Complex III subunits including
      UQCRC2 and regulates CIII assembly/activity; supports a CIII-assembly-relevant
      interaction (but the GO annotation is only bare protein binding).
- id: PMID:36115835
  title: Quantitative fragmentomics allow affinity mapping of interactomes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Affinity fragmentomics; UQCRC2 partners are predominantly PDZ-domain proteins,
      reflecting assay design rather than in vivo mitochondrial interactions.
- id: PMID:8288258
  title: Assignment of the gene for the core protein II (UQCRC2) subunit of the mitochondrial
    cytochrome bc1 complex to human chromosome 16p12.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Gene-mapping paper identifying UQCRC2 as core protein II of the cytochrome bc1
      complex; source of the TAS OXPHOS/aerobic-respiration/inner-membrane
      annotations.
- id: Reactome:R-HSA-164651
  title: Electron transfer from ubiquinol to cytochrome c of complex III
  findings: []
- id: Reactome:R-HSA-9837978
  title: LONP1 binds mitochondrial inner membrane proteins
  findings: []
- id: Reactome:R-HSA-9838004
  title: LONP1 degrades mitochondrial inner membrane proteins
  findings: []
- id: Reactome:R-HSA-9906017
  title: Unknown peptidase cleaves UQCRFS1 subunit
  findings: []
- id: Reactome:R-HSA-9906042
  title: TTC19 clears UQCRFS1 fragments from Complex III
  findings: []