id: Q96D53
gene_symbol: COQ8B
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  COQ8B (ADCK4) is a mitochondrial atypical protein kinase-like enzyme of the
  UbiB/ADCK family and the closest paralog of COQ8A (ADCK3); both are
  co-orthologs of yeast Coq8p. It is required for the biosynthesis of coenzyme Q10
  (ubiquinone), an essential lipid-soluble electron carrier of the respiratory
  chain, and it stabilizes and regulates the multi-subunit COQ metabolon (complex
  Q / CoQ synthome), interacting with COQ6, COQ7 and other COQ enzymes. The
  protein adopts an atypical protein kinase-like fold in which an N-terminal KxGQ
  motif occludes the canonical substrate-binding pocket; nucleotide (ATP) binding
  relieves this autoinhibition. In vitro it binds ATP and phosphorylates the
  metabolon enzyme COQ3, thereby increasing coenzyme Q production, but it does not
  phosphorylate coenzyme Q lipid intermediates and lacks canonical protein kinase
  activity toward general substrates in trans. COQ8B localizes mainly to the
  mitochondrion, associated with the matrix face of the inner mitochondrial
  membrane, and is also detected at the cytosol and cell membrane. It is
  particularly important in kidney podocytes, where it supports podocyte
  migration; loss-of-function mutations cause primary coenzyme Q10 deficiency
  presenting as steroid-resistant nephrotic syndrome with focal segmental
  glomerulosclerosis (nephrotic syndrome type 9).
alternative_products:
- name: '1'
  id: Q96D53-1
- name: '2'
  id: Q96D53-2
  sequence_note: VSP_022357
existing_annotations:
- term:
    id: GO:0006744
    label: ubiquinone biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) propagation of the core UbiB/Coq8-family role in
      ubiquinone biosynthesis. Correct and central to COQ8B function; corroborated
      by experimental IDA/IMP evidence in this gene.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/COQ8B/COQ8B-uniprot.txt
      supporting_text: >-
        Atypical kinase involved in the biosynthesis of coenzyme Q,
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic Subcellular-Location mapping to cytosol. The UniProt record does
      list a cytosolic pool, so this is supported, but the core site of action is
      mitochondrial; keep as a non-core localization.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: file:human/COQ8B/COQ8B-uniprot.txt
      supporting_text: "Cytoplasm, cytosol"
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic Subcellular-Location mapping to plasma/cell membrane. Consistent
      with the experimentally reported podocyte foot-process/cell-membrane pool,
      but non-core relative to the mitochondrial coenzyme Q role.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: file:human/COQ8B/COQ8B-uniprot.txt
      supporting_text: "Cell membrane"
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic Subcellular-Location mapping to mitochondrial membrane; this is
      the core localization and is independently supported by experimental (EXP)
      evidence for this gene.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/COQ8B/COQ8B-uniprot.txt
      supporting_text: "Mitochondrion membrane"
- term:
    id: GO:0006744
    label: ubiquinone biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway-based electronic annotation to ubiquinone biosynthesis. Correct
      and core; redundant with the experimental IDA/IMP annotations.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/COQ8B/COQ8B-uniprot.txt
      supporting_text: "Cofactor biosynthesis; ubiquinone biosynthesis."
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence (HPA) localization to mitochondrion. Consistent with the
      established mitochondrial localization of COQ8B; accept as a core location.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/COQ8B/COQ8B-uniprot.txt
      supporting_text: "Mitochondrion membrane"
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:24270420
  qualifier: located_in
  review:
    summary: >-
      Experimental localization consistent with the podocyte foot-process/cell
      membrane pool reported by Ashraf et al. Real but non-core relative to the
      mitochondrial coenzyme Q role. Experimental annotation retained.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:24270420
      supporting_text: >-
        ADCK4 was expressed in glomerular podocytes and partially localized to
        podocyte mitochondria and foot processes
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: EXP
  original_reference_id: PMID:24270420
  qualifier: located_in
  review:
    summary: >-
      Experimental localization of ADCK4 to podocyte mitochondria. Supports the
      core mitochondrial (inner) membrane localization.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:24270420
      supporting_text: >-
        ADCK4 was expressed in glomerular podocytes and partially localized to
        podocyte mitochondria and foot processes
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: EXP
  original_reference_id: PMID:33988507
  qualifier: located_in
  review:
    summary: >-
      Subcellular-kinome mapping assigning COQ8B to the mitochondrial membrane.
      Consistent with all other localization evidence; core location.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/COQ8B/COQ8B-uniprot.txt
      supporting_text: "Mitochondrion membrane"
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IDA
  original_reference_id: PMID:38425362
  qualifier: enables
  review:
    summary: >-
      Direct in vitro demonstration that COQ8B phosphorylates the COQ metabolon
      enzyme COQ3 at multiple sites in an ATP-dependent manner, increasing
      coenzyme Q production. This is an atypical protein kinase activity (COQ3 as
      substrate); the same study shows it is NOT a small-molecule/lipid kinase.
      Core molecular function; underpins the UniProt EC=2.7.-.- assignment.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:38425362
      supporting_text: >-
        COQ3, but not COQ6, is phosphorylated by COQ8B at multiple sites
- term:
    id: GO:0006744
    label: ubiquinone biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:38425362
  qualifier: involved_in
  review:
    summary: >-
      In vitro reconstitution of the COQ metabolon shows COQ8B increases and
      streamlines coenzyme Q production. Direct experimental support for the core
      ubiquinone biosynthetic process role.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:38425362
      supporting_text: >-
        We demonstrate that COQ8, a kinase, increases and streamlines coenzyme Q
        production
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput mitochondrial proteome dataset placing COQ8B in the
      mitochondrion. Consistent with the well-established mitochondrial
      localization; accept.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/COQ8B/COQ8B-uniprot.txt
      supporting_text: "Mitochondrion membrane"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:33988507
  qualifier: located_in
  review:
    summary: >-
      Direct localization to mitochondrion from the subcellular kinome map.
      Consistent with all other evidence; core location.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/COQ8B/COQ8B-uniprot.txt
      supporting_text: "Mitochondrion membrane"
- term:
    id: GO:0008289
    label: lipid binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Sequence-similarity inference of lipid binding. COQ8-family proteins do bind
      coenzyme Q lipid intermediates and associate with membrane lipids, so this
      is biologically plausible, but it is a supporting/inferred binding property
      rather than the core catalytic function. Keep as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:27499294
      supporting_text: >-
        COQ8 has ATPase activity and interacts with lipid CoQ intermediates
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Sequence-similarity inference of ATPase (ATP hydrolysis) activity. ATPase
      activity was directly demonstrated for the paralog COQ8A/yeast Coq8p and is
      consistent with the nucleotide-gated atypical-kinase mechanism, so this is
      well-founded. For COQ8B the physiologically relevant catalytic output is
      COQ3 phosphorylation; keep the ATPase MF as a supporting/non-core activity.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:27499294
      supporting_text: >-
        COQ8 has ATPase activity and interacts with lipid CoQ intermediates
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IDA
  original_reference_id: PMID:27499294
  qualifier: enables
  negated: true
  review:
    summary: >-
      NOT annotation: family-level biochemical assays (COQ8A/yeast Coq8p, applied
      to COQ8B by the naming/orthology framework of this paper) showed no
      canonical protein kinase activity in trans toward general substrates. This
      negation is correctly recorded and refers to general in-trans kinase
      behaviour; it does not contradict the later, specific ATP-dependent COQ3
      phosphorylation by COQ8B (PMID:38425362). Retained as a NOT annotation.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:27499294
      supporting_text: >-
        we demonstrate that it lacks canonical protein kinase activity in trans
- term:
    id: GO:0006468
    label: protein phosphorylation
  evidence_type: IDA
  original_reference_id: PMID:27499294
  qualifier: involved_in
  negated: true
  review:
    summary: >-
      NOT annotation paralleling the NOT protein kinase activity: no general
      in-trans protein phosphorylation was detected for the COQ8 family in this
      study. Correctly recorded; the specific COQ3 phosphorylation by COQ8B
      (PMID:38425362) is a distinct, later finding on a defined substrate.
      Retained as a NOT annotation.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:27499294
      supporting_text: >-
        we demonstrate that it lacks canonical protein kinase activity in trans
- term:
    id: GO:0006744
    label: ubiquinone biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:27499294
  qualifier: involved_in
  review:
    summary: >-
      Mutant-phenotype evidence that loss of COQ8 function disrupts the CoQ
      biosynthesis complex (complex Q) and coenzyme Q production. Supports the
      core ubiquinone biosynthetic process role. Experimental IMP retained.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:27499294
      supporting_text: >-
        Coq8p and COQ8A specifically maintain complex Q in yeast and mammals
- term:
    id: GO:0021692
    label: cerebellar Purkinje cell layer morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:27499294
  qualifier: involved_in
  review:
    summary: >-
      The cerebellar Purkinje-cell phenotype in PMID:27499294 is that of the mouse
      Coq8a (COQ8A/ADCK3) knockout, not COQ8B; COQ8B loss-of-function disease is
      renal (steroid-resistant nephrotic syndrome / FSGS), not cerebellar. This
      IMP therefore appears to reflect the paralog rather than COQ8B and is an
      over-annotation. As an experimental annotation it is not removed, but it is
      flagged as over-annotated / likely paralog mis-attribution.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:27499294
      supporting_text: >-
        Coq8a−/− mice showed a specific defect in the cerebellar Purkinje cell (PC)
        layer
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: file:human/COQ8B/COQ8B-uniprot.txt
  qualifier: enables
  review:
    summary: >-
      ATP binding is not among the GOA TSV rows but is strongly supported by the
      UniProt record: multiple annotated ATP BINDING sites and a nucleotide-gated
      mechanism in which nucleotide binding relieves KxGQ autoinhibition and opens
      the substrate-binding pocket. Core molecular function; proposed as a new
      annotation.
    action: NEW
    supported_by:
    - reference_id: file:human/COQ8B/COQ8B-uniprot.txt
      supporting_text: >-
        Nucleotide-binding opens the substrate binding pocket
references:
- id: file:human/COQ8B/COQ8B-uniprot.txt
  title: UniProt entry Q96D53 (COQ8B_HUMAN)
  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:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  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:24270420
  title: ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10
    biosynthesis disruption.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Defining COQ8B/ADCK4 paper: mutations cause steroid-resistant nephrotic
      syndrome via CoQ10 biosynthesis disruption; establishes podocyte expression,
      partial mitochondrial/foot-process localization, interaction with COQ6/COQ7,
      and a podocyte-migration requirement. PubMed abstract verified against cached
      record; supports the disease, localization, and CoQ-biosynthesis annotations.
- id: PMID:27499294
  title: Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase
    Activity.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary focus is the paralog COQ8A (ADCK3)/yeast Coq8p; proposes the
      ADCK3->COQ8A and ADCK4->COQ8B renaming. Full text available and verified.
      Correctly supports the family-level NOT canonical protein kinase activity in
      trans, ATPase activity, lipid CoQ-intermediate binding, and CoQ-biosynthesis
      role. The cerebellar Purkinje-cell phenotype it reports is the mouse Coq8a
      knockout, so the GO:0021692 IMP transferred to human COQ8B is a likely
      paralog mis-attribution (marked over-annotated), not a citation error.
- id: PMID:33988507
  title: A subcellular map of the human kinome.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Systematic subcellular localization map of the human kinome; gene-level
      COQ8B assignment (mitochondrion / mitochondrial membrane) is in the
      dataset/supplementary rather than the extractable main text. Supports the
      mitochondrial localization annotations. Abstract verified.
- 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: >-
      High-throughput mitochondrial proteome resource; supports mitochondrial
      localization of COQ8B via the dataset. Gene-specific evidence is in the
      supplementary proteome, not the extractable main text.
- id: PMID:38425362
  title: In vitro construction of the COQ metabolon unveils the molecular determinants
    of coenzyme Q biosynthesis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      In vitro COQ metabolon reconstitution. Directly demonstrates COQ8B is an
      ATP-dependent COQ3 protein kinase that increases coenzyme Q production, and
      that it is NOT a small-molecule/lipid kinase (no phosphorylated CoQ
      intermediates). Full text available; quotes verified verbatim. Basis for the
      UniProt EC=2.7.-.- and the protein kinase activity / ubiquinone biosynthesis
      IDA annotations.
core_functions:
- description: >-
    ATP-dependent atypical protein kinase that phosphorylates the coenzyme Q
    biosynthesis (COQ metabolon) enzyme COQ3, thereby promoting ubiquinone
    (coenzyme Q10) production; nucleotide binding relieves KxGQ-mediated
    autoinhibition of the atypical kinase fold.
  molecular_function:
    id: GO:0004672
    label: protein kinase activity
  directly_involved_in:
  - id: GO:0006744
    label: ubiquinone biosynthetic process
  locations:
  - id: GO:0031966
    label: mitochondrial membrane
  - id: GO:0005739
    label: mitochondrion
  supported_by:
  - reference_id: PMID:38425362
    supporting_text: >-
      COQ3, but not COQ6, is phosphorylated by COQ8B at multiple sites
  - reference_id: file:human/COQ8B/COQ8B-uniprot.txt
    supporting_text: >-
      as a protein kinase that mediates phosphorylation of COQ3
- description: >-
    Binds ATP; nucleotide binding opens the substrate-binding pocket of the
    autoinhibited atypical kinase fold, gating its catalytic activity in coenzyme
    Q biosynthesis.
  molecular_function:
    id: GO:0005524
    label: ATP binding
  directly_involved_in:
  - id: GO:0006744
    label: ubiquinone biosynthetic process
  locations:
  - id: GO:0031966
    label: mitochondrial membrane
  supported_by:
  - reference_id: file:human/COQ8B/COQ8B-uniprot.txt
    supporting_text: >-
      Nucleotide-binding opens the substrate binding pocket