cia30

id: O42636
gene_symbol: cia30
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:367110
  label: Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257
    / FGSC 987)
description: >-
  Neurospora crassa CIA30 (Complex I intermediate-associated protein 30, also known as
  cia35) is a mitochondrial chaperone specifically involved in the assembly of NADH:ubiquinone
  oxidoreductase (complex I). CIA30 is the founding member of the CIA30/NDUFAF1 family and
  was identified as one of two novel extra proteins (30 kDa and 84 kDa) that associate with
  the large membrane arm assembly intermediate of complex I but are not constituent parts
  of the mature complex (PMID:9769214). Disruption mutants accumulate the matrix arm and the
  small membrane arm assembly intermediate but cannot form the large membrane arm intermediate.
  Pulse-chase experiments showed that CIA30 is repeatedly involved in many assembly cycles,
  consistent with chaperone function (PMID:9769214). While described as a "chaperone" in the
  original paper, CIA30 functions specifically as a complex I assembly factor rather than as
  a general unfolded protein binding protein. The GO:0051082 annotation reflects binding to
  unassembled complex I subunits during assembly, which is a specific assembly chaperone
  function, not general unfolded protein binding.
existing_annotations:
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for mitochondrion localization. CIA30 is a mitochondrial protein,
      confirmed by direct experimental evidence (PMID:9769214). UniProt lists mitochondrion
      as the subcellular location and the protein has a mitochondrial transit peptide
      (residues 1-8). The IBA annotation is consistent with the IEA annotation from
      UniProt and the experimental evidence.
    action: ACCEPT
    reason: >-
      Mitochondrial localization is the primary and only documented location of CIA30,
      directly demonstrated in PMID:9769214. The protein has a mitochondrial transit
      peptide. Core localization annotation.
- term:
    id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for mitochondrial electron transport, NADH to ubiquinone. CIA30 is
      required for assembly of complex I, which performs NADH:ubiquinone oxidoreduction.
      Without CIA30, the large membrane arm intermediate cannot be formed, and the mature
      complex I is not assembled (PMID:9769214). CIA30 is not a subunit of the mature
      complex but is essential for its assembly. The IBA annotation is appropriate as
      CIA30 is involved in the pathway, albeit indirectly through its assembly function.
    action: ACCEPT
    reason: >-
      CIA30 is essential for complex I assembly (PMID:9769214). While not a subunit of
      the mature complex, its loss prevents proper complex I formation and thus NADH to
      ubiquinone electron transport. The IBA annotation appropriately captures this
      involvement.
    supported_by:
      - reference_id: PMID:9769214
        supporting_text: >-
          Mutants generated by disrupting the genes of either of the two proteins accumulate
          the matrix arm of complex I and the small membrane arm assembly intermediate, but are
          incapable of forming the large intermediate
- term:
    id: GO:0010257
    label: NADH dehydrogenase complex assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for NADH dehydrogenase complex assembly. This is the core biological
      process function of CIA30. PMID:9769214 directly demonstrated that CIA30 is required
      for assembly of the large membrane arm intermediate of complex I, and pulse-chase
      experiments showed it participates in repeated assembly cycles. The IBA annotation is
      consistent with the NAS annotation for the more specific GO:0032981 term.
    action: ACCEPT
    reason: >-
      NADH dehydrogenase complex assembly is the core function of CIA30. Directly
      demonstrated by disruption mutants that fail to form the large membrane arm
      intermediate (PMID:9769214). The IBA is well supported and phylogenetically
      appropriate for the CIA30/NDUFAF1 family.
    supported_by:
      - reference_id: PMID:9769214
        supporting_text: >-
          Mutants generated by disrupting the genes of either of the two proteins accumulate
          the matrix arm of complex I and the small membrane arm assembly intermediate, but are
          incapable of forming the large intermediate
      - reference_id: PMID:9769214
        supporting_text: >-
          Pulse-chase labelling experiments showed that the two proteins are repeatedly involved
          in many assembly cycles of the intermediate
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for unfolded protein binding. GO:0051082 is proposed for obsoletion
      (go-ontology#30962). CIA30 was described as a "novel chaperone" in the original
      publication (PMID:9769214), but its function is specifically as a complex I assembly
      factor, not as a general unfolded protein binding protein. CIA30 associates exclusively
      with the large membrane arm assembly intermediate of complex I and participates in
      repeated assembly cycles (PMID:9769214). This is a specific assembly chaperone function
      rather than general unfolded protein binding. The term "chaperone" as used in the
      original paper refers to the specific assembly assistance role, not to broad unfolded
      protein recognition. Per UPB project rules, specific assembly chaperones that are not
      general unfolded protein binding proteins should be marked as over-annotated or
      modified.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      CIA30 is a specific complex I assembly factor, not a general unfolded protein binding
      protein. While described as a "chaperone" in PMID:9769214, this refers to its specific
      role in complex I membrane arm assembly -- it associates exclusively with the large
      membrane arm assembly intermediate and does not bind unfolded proteins generally. The
      GO:0051082 annotation overstates the generality of CIA30's binding specificity. The
      complex I assembly function is already captured by GO:0010257 and GO:0032981.
    supported_by:
      - reference_id: PMID:9769214
        supporting_text: >-
          In the wild-type, the extra proteins exclusively associate with the large membrane arm
          assembly intermediate
      - reference_id: PMID:9769214
        supporting_text: >-
          These results indicate that the two proteins are novel chaperones specific for complex
          I membrane arm assembly
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation for mitochondrion from UniProt subcellular location mapping. Consistent
      with the IBA annotation for the same term and the direct experimental evidence from
      PMID:9769214. UniProt lists mitochondrion as the subcellular location.
    action: ACCEPT
    reason: >-
      Consistent with IBA annotation and direct experimental evidence. Mitochondrion is
      the primary and only documented location of CIA30.
- term:
    id: GO:0032981
    label: mitochondrial respiratory chain complex I assembly
  evidence_type: NAS
  original_reference_id: PMID:9769214
  review:
    summary: >-
      NAS annotation for mitochondrial respiratory chain complex I assembly from PMID:9769214.
      This is the core biological process function of CIA30. The original paper titled
      "Involvement of two novel chaperones in the assembly of mitochondrial NADH:Ubiquinone
      oxidoreductase (complex I)" directly describes the role of CIA30 in complex I assembly.
      The NAS evidence code is appropriate as the paper provides direct experimental evidence
      for complex I assembly involvement. This is a more specific child of GO:0010257.
    action: ACCEPT
    reason: >-
      Complex I assembly is the core function of CIA30. PMID:9769214 directly demonstrated
      this through disruption mutants, pulse-chase experiments, and co-purification with
      assembly intermediates. This more specific term (child of GO:0010257) appropriately
      captures the respiratory chain complex I assembly function.
    supported_by:
      - reference_id: PMID:9769214
        supporting_text: >-
          These results indicate that the two proteins are novel chaperones specific for complex
          I membrane arm assembly
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:9769214
  review:
    summary: >-
      IDA annotation for unfolded protein binding from PMID:9769214. GO:0051082 is proposed
      for obsoletion (go-ontology#30962). The original paper demonstrated that CIA30
      associates with the large membrane arm assembly intermediate of complex I and is
      involved in repeated assembly cycles (PMID:9769214: "the extra proteins exclusively
      associate with the large membrane arm assembly intermediate" and "Pulse-chase labelling
      experiments showed that the two proteins are repeatedly involved in many assembly
      cycles"). The authors called CIA30 a "chaperone" but specified it was "specific for
      complex I membrane arm assembly." This is a specific assembly factor function, not
      general unfolded protein binding. The protein does not bind unfolded proteins broadly
      -- it binds specifically to complex I assembly intermediates. The IDA evidence
      demonstrates complex I assembly intermediate binding, not general unfolded protein
      binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The IDA evidence from PMID:9769214 demonstrates that CIA30 binds specifically to
      complex I assembly intermediates, not to unfolded proteins generally. The original
      paper explicitly states the proteins are "chaperones specific for complex I membrane
      arm assembly." GO:0051082 overstates the generality of the binding. The complex I
      assembly function is better captured by GO:0032981 and GO:0010257. While CIA30 may
      indeed interact with unfolded or partially assembled complex I subunits, calling
      this "unfolded protein binding" conflates a specific assembly factor role with
      general chaperone function.
    supported_by:
      - reference_id: PMID:9769214
        supporting_text: >-
          In the wild-type, the extra proteins exclusively associate with the large membrane arm
          assembly intermediate
      - reference_id: PMID:9769214
        supporting_text: >-
          Pulse-chase labelling experiments showed that the two proteins are repeatedly involved
          in many assembly cycles of the intermediate
      - reference_id: PMID:9769214
        supporting_text: >-
          These results indicate that the two proteins are novel chaperones specific for complex
          I membrane arm assembly
core_functions:
- molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  description: >-
    CIA30 functions as a specific assembly chaperone for complex I membrane arm formation.
    It associates with the large membrane arm assembly intermediate and participates in
    repeated assembly cycles (PMID:9769214). The "chaperone" designation reflects its role
    in assisting complex I subunit assembly rather than general unfolded protein binding.
    While GO:0044183 is used as the closest available MF term, CIA30's function is more
    specifically as an assembly factor than as a general protein folding chaperone.
  directly_involved_in:
    - id: GO:0032981
      label: mitochondrial respiratory chain complex I assembly
    - id: GO:0006120
      label: mitochondrial electron transport, NADH to ubiquinone
  locations:
    - id: GO:0005739
      label: mitochondrion
  supported_by:
    - reference_id: PMID:9769214
      supporting_text: >-
        These results indicate that the two proteins are novel chaperones specific for complex
        I membrane arm assembly
    - reference_id: PMID:9769214
      supporting_text: >-
        Pulse-chase labelling experiments showed that the two proteins are repeatedly involved
        in many assembly cycles of the intermediate
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: PMID:9769214
  title: Involvement of two novel chaperones in the assembly of mitochondrial NADH:Ubiquinone
    oxidoreductase (complex I).
  findings: []