id: Q6DKK2
gene_symbol: TTC19
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  TTC19 (tetratricopeptide repeat protein 19, mitochondrial) is a nuclear-encoded,
  mitochondrion-imported protein of the mitochondrial inner membrane that acts as an
  assembly/maintenance factor for respiratory Complex III (cytochrome bc1, ubiquinol-cytochrome
  c reductase). It is a tetratricopeptide-repeat (TPR) scaffold protein containing five TPR
  repeats and has no catalytic activity of its own. TTC19 binds the mature Complex III dimer
  after incorporation of the Rieske iron-sulfur protein UQCRFS1, and is required for the
  clearance/turnover of the UQCRFS1 N-terminal fragments generated during Rieske maturation;
  accumulation of these fragments is detrimental to Complex III activity, so TTC19 preserves the
  structural and functional integrity of the complex. Loss-of-function mutations cause
  mitochondrial complex III deficiency, nuclear type 2 (MC3DN2), a progressive neurological
  disorder with encephalopathy, ataxia, psychomotor regression, and psychiatric features.
existing_annotations:
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetically inferred localization of TTC19 to the mitochondrial inner membrane. This
      is consistent with experimental evidence that TTC19 is an inner-membrane-embedded Complex
      III assembly factor and is the correct, specific compartment for this protein.
    action: ACCEPT
    reason: >-
      The inner-membrane localization is directly supported by experimental data (PMID:21278747)
      and by the protein's role as a Complex III assembly factor; the IBA call is appropriate and
      at the correct level of specificity.
    supported_by:
    - reference_id: PMID:21278747
      supporting_text: inner mitochondrial membrane as part of two high-molecular-weight complexes
- term:
    id: GO:0034551
    label: mitochondrial respiratory chain complex III assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically inferred involvement of TTC19 in mitochondrial respiratory chain complex
      III assembly. This matches the experimentally established core function of TTC19 as a
      Complex III assembly/maintenance factor and is supported by the Drosophila ortholog.
    action: ACCEPT
    reason: >-
      This is the core biological process for TTC19, supported experimentally in humans and flies
      (PMID:21278747). The IBA term is at the appropriate level of specificity and is retained as
      a core function.
    supported_by:
    - reference_id: PMID:21278747
      supporting_text: TTC19 is a putative cIII assembly factor
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation of inner-membrane localization derived from the UniProt Subcellular
      Location vocabulary mapping. It agrees with the curated experimental localization.
    action: ACCEPT
    reason: >-
      Correct and consistent with experimental IDA evidence (PMID:21278747); the SubCell-derived
      IEA is at the correct level of specificity.
    supported_by:
    - reference_id: file:human/TTC19/TTC19-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0034551
    label: mitochondrial respiratory chain complex III assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic annotation mapping the TTC19 InterPro signature (IPR040395) to
      mitochondrial respiratory chain complex III assembly. This matches the experimentally
      established function.
    action: ACCEPT
    reason: >-
      The InterPro family is TTC19-specific (IPR040395 TTC19) and the mapping to Complex III
      assembly is biologically correct and supported by experimental evidence (PMID:21278747).
    supported_by:
    - reference_id: PMID:21278747
      supporting_text: TTC19 is a putative cIII assembly factor
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16713569
  qualifier: enables
  review:
    summary: >-
      Binary interaction of TTC19 captured in a yeast two-hybrid interactome for inherited
      ataxias (partner ATXN1, P54253). Bare "protein binding" is uninformative about molecular
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 "protein binding" does not convey a specific molecular function and is derived
      from a large-scale interaction screen. Per curation guidance, bare protein-binding IPIs are
      retained but flagged as over-annotated rather than removed; the informative function is
      captured by the Complex III assembly annotations.
    supported_by:
    - reference_id: PMID:16713569
      supporting_text: protein-protein interactions using a stringent yeast two-hybrid screen
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23414517
  qualifier: enables
  review:
    summary: >-
      Interaction of TTC19 reported in a skeletal-muscle (LGMD) interactome dataset (partner TCAP,
      O15273). Bare "protein binding" is uninformative about TTC19's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      A high-throughput interactome-derived protein-binding IPI; retained but marked as
      over-annotated because it adds no specific functional information beyond the curated
      Complex III role.
    supported_by:
    - reference_id: PMID:23414517
      supporting_text: LGMD interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      Interactions of TTC19 captured in a proteome-scale binary interactome map (HuRI-type
      screen). Bare "protein binding" is uninformative about molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Large-scale interactome-derived protein-binding IPI; retained but flagged as over-annotated
      since it provides no specific molecular-function detail.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: A proteome-scale map of the human interactome network
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      Interactions of TTC19 from a large-scale interactome ("protein communities and disease
      networks") study. Bare "protein binding" is uninformative about molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-throughput interactome-derived protein-binding IPI; retained but marked as
      over-annotated because it does not specify a molecular function.
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: Architecture of the human interactome defines protein communities and disease
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31617661
  qualifier: enables
  review:
    summary: >-
      TTC19 identified as a proximity/interaction partner (with HTRA2, O43464) in a BioID map of
      mitochondrial intermembrane-space proteases. Bare "protein binding" is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Proximity-labeling-derived protein-binding IPI; retained but flagged as over-annotated. It
      is consistent with TTC19's mitochondrial localization but adds no specific molecular
      function.
    supported_by:
    - reference_id: PMID:31617661
      supporting_text: biotinylation (BioID) is used to map the interactomes
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Numerous binary interactions of TTC19 captured in a reference human binary interactome map.
      Bare "protein binding" is uninformative about molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Large-scale binary-interactome-derived protein-binding IPI (many partners); retained but
      marked as over-annotated because it provides no specific molecular-function information.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: >-
      TTC19 interactions reported in a neurodegenerative-disease protein interaction network.
      Bare "protein binding" is uninformative about molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Interactome-derived protein-binding IPI; retained but flagged as over-annotated as it
      conveys no specific molecular function.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      TTC19 interactions captured in cell-specific proteome-scale interactome networks (BioPlex).
      Bare "protein binding" is uninformative about molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Large-scale AP-MS interactome-derived protein-binding IPI; retained but marked as
      over-annotated because it provides no specific molecular-function information.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Dual proteome-scale networks reveal cell-specific remodeling of the human
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence-based (Human Protein Atlas) localization of TTC19 to the mitochondrion.
      Correct but less specific than the inner-membrane annotation.
    action: ACCEPT
    reason: >-
      Consistent with the established mitochondrial localization of TTC19. It is accurate though
      more general than the mitochondrial inner membrane annotation, which better captures the
      protein's precise location.
    supported_by:
    - reference_id: PMID:21278747
      supporting_text: inner mitochondrial membrane as part of two high-molecular-weight complexes
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput identification of TTC19 in a high-confidence human mitochondrial proteome
      (MitoCoP). Confirms mitochondrial localization at the organelle level.
    action: ACCEPT
    reason: >-
      TTC19 is a bona fide mitochondrial protein; this proteomics-based organelle-level
      localization is correct, though less specific than the inner-membrane annotation.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP)
- term:
    id: GO:0000281
    label: mitotic cytokinesis
  evidence_type: TAS
  original_reference_id: PMID:20208530
  qualifier: involved_in
  review:
    summary: >-
      Proposed role for TTC19 in cytokinesis, as a ZFYVE26 (FYVE-CENT) binding partner interacting
      with the ESCRT-III subunit CHMP4B at the midbody. This is not the core mitochondrial function
      of TTC19 and is disputed.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This assignment rests on a single study (PMID:20208530); UniProt records a CAUTION that the
      midbody localization underpinning this cytokinesis role could not be confirmed by others
      (PMID:21278747), and the well-established function of TTC19 is as a mitochondrial inner-membrane
      Complex III assembly factor. The annotation is retained but flagged as an over-annotation
      rather than removed, since the underlying interaction was experimentally reported.
    supported_by:
    - reference_id: PMID:20208530
      supporting_text: TTC19, which in turn interacts with CHMP4B, an endosomal sorting
    - reference_id: file:human/TTC19/TTC19-uniprot.txt
      supporting_text: the midbody localization could not be
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20208530
  qualifier: enables
  review:
    summary: >-
      Interaction of TTC19 with ZFYVE26/FYVE-CENT (Q68DK2) and CHMP4B (Q9H444) reported in the
      cytokinesis study. Bare "protein binding" is uninformative about molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      A specific reported interaction, but captured only as the uninformative GO:0005515; retained
      per curation guidance but marked as over-annotated. The associated cytokinesis role is itself
      disputed (see UniProt CAUTION, PMID:21278747).
    supported_by:
    - reference_id: PMID:20208530
      supporting_text: binding partner TTC19
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:21278747
  qualifier: located_in
  review:
    summary: >-
      Direct experimental evidence that TTC19 is embedded in the mitochondrial inner membrane, as
      part of high-molecular-weight complexes one of which coincides with Complex III.
    action: ACCEPT
    reason: >-
      This is the primary experimental source establishing TTC19's inner-membrane localization and
      is a core, well-supported annotation.
    supported_by:
    - reference_id: PMID:21278747
      supporting_text: inner mitochondrial membrane as part of two high-molecular-weight complexes, one of which coincides with cIII
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: TAS
  original_reference_id: PMID:20208530
  qualifier: located_in
  review:
    summary: >-
      Reported centrosomal localization of TTC19 during the cell cycle from the cytokinesis study.
      This is inconsistent with TTC19's established role as a mitochondrial inner-membrane protein.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Based on a single study (PMID:20208530); UniProt notes a CAUTION that the associated
      midbody localization could not be confirmed by others (PMID:21278747), and TTC19 is firmly
      established as a mitochondrial inner-membrane protein. Flagged as over-annotation rather than
      removed, since the localization was experimentally reported.
    supported_by:
    - reference_id: file:human/TTC19/TTC19-uniprot.txt
      supporting_text: the midbody localization could not be
    - reference_id: PMID:20208530
      supporting_text: recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19
- term:
    id: GO:0030496
    label: midbody
  evidence_type: TAS
  original_reference_id: PMID:20208530
  qualifier: located_in
  review:
    summary: >-
      Reported recruitment of TTC19 to the midbody during cytokinesis. UniProt explicitly notes
      that this midbody localization could not be confirmed by others.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Single-study localization (PMID:20208530) that is contradicted by follow-up work
      (PMID:21278747, per the UniProt CAUTION) and is inconsistent with TTC19's mitochondrial
      inner-membrane biology. Retained but flagged as over-annotation rather than removed.
    supported_by:
    - reference_id: file:human/TTC19/TTC19-uniprot.txt
      supporting_text: the midbody localization could not be
    - reference_id: PMID:20208530
      supporting_text: Translocation of FYVE-CENT and TTC19 from the centrosome to
- term:
    id: GO:0034551
    label: mitochondrial respiratory chain complex III assembly
  evidence_type: IMP
  original_reference_id: PMID:21278747
  qualifier: involved_in
  review:
    summary: >-
      Direct genetic/mutational evidence that loss of TTC19 causes Complex III deficiency with
      accumulation of cIII-specific assembly intermediates in humans and flies, establishing TTC19
      as a Complex III assembly factor.
    action: ACCEPT
    reason: >-
      This is the core, experimentally established function of TTC19 and is well supported by the
      disease-causing loss-of-function mutations and the Drosophila knockout phenotype. It is
      retained as the primary core function.
    supported_by:
    - reference_id: PMID:21278747
      supporting_text: profound cIII deficiency and accumulation of cIII-specific assembly intermediates
core_functions:
- description: >-
    Mitochondrial inner-membrane tetratricopeptide-repeat assembly/maintenance factor for
    respiratory Complex III (cytochrome bc1); required for turnover of UQCRFS1 (Rieske) N-terminal
    fragments to preserve Complex III integrity. Non-catalytic scaffold protein.
  directly_involved_in:
  - id: GO:0034551
    label: mitochondrial respiratory chain complex III assembly
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:21278747
    supporting_text: TTC19 is a putative cIII assembly factor
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- 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: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:16713569
  title: A protein-protein interaction network for human inherited ataxias and disorders
    of Purkinje cell degeneration.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale yeast two-hybrid ataxia interactome; TTC19 appears as an interactor (ATXN1).
      Supports only a bare protein-binding annotation, not a specific function.
- id: PMID:20208530
  title: PtdIns(3)P controls cytokinesis through KIF13A-mediated recruitment of FYVE-CENT
    to the midbody.
  findings: []
  reference_review:
    relevance: LOW
    correctness: DISPUTED
    review_notes: >-
      Reports TTC19 as a ZFYVE26/CHMP4B partner with centrosome/midbody localization and a
      cytokinesis role. UniProt records a CAUTION that the midbody localization could not be
      confirmed by others (PMID:21278747); not the core mitochondrial function of TTC19.
- id: PMID:21278747
  title: Mutations in TTC19 cause mitochondrial complex III deficiency and neurological
    impairment in humans and flies.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Discovery paper establishing TTC19 as a mitochondrial inner-membrane Complex III assembly
      factor and cause of MC3DN2; source for the core inner-membrane and cIII-assembly annotations.
- id: PMID:23414517
  title: 'A human skeletal muscle interactome centered on proteins involved in muscular
    dystrophies: LGMD interactome.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Skeletal-muscle interactome; TTC19 appears as an interactor (TCAP). Supports only a bare
      protein-binding annotation.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale binary interactome; source of high-throughput protein-binding IPIs for TTC19.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale interactome; source of high-throughput protein-binding IPIs for TTC19.
- id: PMID:31617661
  title: Global Interactome Mapping of Mitochondrial Intermembrane Space Proteases
    Identifies a Novel Function for HTRA2.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioID interactome of mitochondrial IMS proteases; TTC19 appears as a proximity partner
      (HTRA2). Consistent with mitochondrial localization but supports only bare protein binding.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Reference binary interactome; source of numerous high-throughput protein-binding IPIs for TTC19.
- 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: >-
      Neurodegenerative-disease interactome; source of high-throughput protein-binding IPIs for TTC19.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioPlex AP-MS interactome; source of high-throughput protein-binding IPIs for TTC19.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      MitoCoP high-confidence mitochondrial proteome; corroborates TTC19 as a bona fide
      mitochondrial protein (organelle-level localization).
- id: file:human/TTC19/TTC19-uniprot.txt
  title: UniProtKB entry Q6DKK2 (TTC19_HUMAN)
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      UniProt FUNCTION/SUBUNIT/SUBCELLULAR LOCATION/CAUTION for TTC19, summarizing the
      Complex III husbandry role (UQCRFS1 fragment clearance) and the disputed cytokinesis role.