id: P61457
gene_symbol: PCBD1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PCBD1 is a small (104-residue) bifunctional, moonlighting protein that
  assembles as a homodimer/homotetramer and is distributed between the cytosol
  and the nucleus. It has two well-established, mechanistically unrelated
  activities. (1) As an enzyme, pterin-4-alpha-carbinolamine dehydratase (PCD;
  also called phenylalanine hydroxylase-stimulating protein, PHS; EC 4.2.1.96),
  it catalyzes the dehydration of (4aS,6R)-4a-hydroxy-tetrahydrobiopterin to
  quinonoid-6,7-dihydrobiopterin plus water. 4a-hydroxy-tetrahydrobiopterin is
  the carbinolamine intermediate formed when tetrahydrobiopterin (BH4) serves as
  cofactor for the aromatic amino acid hydroxylases, most prominently during the
  phenylalanine hydroxylase (PAH)-catalyzed conversion of phenylalanine to
  tyrosine. The quinonoid dihydrobiopterin product is subsequently reduced back
  to BH4 by dihydropteridine reductase (QDPR/DHPR); PCBD1 therefore operates in
  the BH4 regeneration/recycling arm of the cofactor cycle, accelerating
  quinonoid-BH2 formation and suppressing the non-enzymatic rearrangement that
  yields 7-substituted (primapterin) pterins. (2) As the dimerization cofactor of
  HNF1 (DCoH), the same protein binds and stabilizes the homodimer of the
  homeodomain transcription factors HNF1A and HNF1B; it does not bind DNA itself
  and does not alter HNF1 DNA-binding, but the resulting tetrameric DCoH-HNF1
  complex has enhanced transcriptional activity. Through this HNF1B coactivator
  role PCBD1 supports transcription of targets such as FXYD2 in the renal distal
  convoluted tubule, linking it to renal magnesium handling and to
  HNF1-dependent gene programs in kidney and pancreas. Loss-of-function variants
  cause an autosomal-recessive hyperphenylalaninemia (HPABH4D, primapterinuria),
  classically a mild/transient neonatal hyperphenylalaninemia, with later
  HNF1-associated complications including hypomagnesemia with renal magnesium
  wasting and MODY-type diabetes.
existing_annotations:
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation placing PCBD1 in the nucleoplasm. This is
      consistent with the DCoH/coactivator role, where PCBD1 is recruited to the
      nucleus via HNF1 and acts on HNF1-dependent transcription.
    action: ACCEPT
    reason: >-
      Nuclear localization is experimentally supported for human PCBD1 and its
      DCoH function requires the nucleus. PCBD1 is recruited to the nucleus
      through interaction with HNF1B.
    supported_by:
    - reference_id: PMID:24204001
      supporting_text: >-
        Furthermore, cytosolic localization of PCBD1 increased when coexpressed
        with HNF1B mutants.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation to the cytosol, the compartment where the
      dehydratase reaction of the BH4 cycle takes place and where PCBD1
      homotetramers accumulate.
    action: ACCEPT
    reason: >-
      Cytosolic localization is experimentally confirmed for PCBD1 and is where
      its enzymatic (PCD) function operates as part of the BH4 regeneration
      cycle. PCBD1 was described as present in the cytosol of renal cells.
    supported_by:
    - reference_id: PMID:24204001
      supporting_text: >-
        Because Pcbd1 was present in the cytosol of renal cells, we hypothesized
        that the relative abundance of PCBD1 and HNF1B in the kidney may favor
        the cytosolic localization.
- term:
    id: GO:0008124
    label: 4-alpha-hydroxytetrahydrobiopterin dehydratase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) annotation to the defining catalytic activity of the
      protein family, pterin-4-alpha-carbinolamine dehydratase (EC 4.2.1.96).
      This is one of the two core functions of PCBD1.
    action: ACCEPT
    reason: >-
      This is the core enzymatic function. UniProt records the catalytic
      activity (RHEA:11920; EC 4.2.1.96), disease variants reduce dehydratase
      activity, and the family (Pterin_4a, IPR001533) is defined by this
      reaction. Well supported across evidence types (IBA, IEA, ISS).
    supported_by:
    - reference_id: PMID:24204001
      supporting_text: >-
        Mutations in PCBD1 have been shown to cause a transient and benign form
        of neonatal HPABH4D.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic (IEA) annotation to nucleus, redundant with and corroborated by
      the experimental EXP nuclear annotation from PMID:24204001.
    action: ACCEPT
    reason: >-
      Nuclear localization is experimentally established for PCBD1 (recruited via
      HNF1B) and required for its coactivator function.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic (IEA) annotation from the UniProt Subcellular Location mapping
      to cytoplasm, corroborated by experimental data.
    action: ACCEPT
    reason: >-
      Cytoplasmic/cytosolic localization is experimentally established and is the
      site of the dehydratase reaction. Redundant with the more specific cytosol
      annotations but not incorrect.
- term:
    id: GO:0006571
    label: L-tyrosine biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation created by inter-ontology logical inference
      (GO_REF:0000108) from the (erroneous) molecular function GO:0004505
      phenylalanine 4-monooxygenase activity. PCBD1 is not a tyrosine
      biosynthetic enzyme.
    action: REMOVE
    reason: >-
      This annotation is a downstream logical consequence of the incorrect
      phenylalanine 4-monooxygenase activity assignment (see GO:0004505). Tyrosine
      is produced by phenylalanine hydroxylase (PAH), which uses BH4 as cofactor;
      PCBD1 instead dehydrates the 4a-hydroxy-BH4 product of that hydroxylation
      as part of BH4 regeneration. It does not catalyze or participate in tyrosine
      biosynthesis. Since the source molecular function is wrong for PCBD1, the
      inferred process should be removed.
- term:
    id: GO:0006729
    label: tetrahydrobiopterin biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro-based electronic annotation to tetrahydrobiopterin biosynthetic
      process. PCBD1 participates in the BH4 cycle, regenerating BH4 from the
      4a-hydroxy-BH4 carbinolamine formed during aromatic amino acid
      hydroxylation.
    action: ACCEPT
    reason: >-
      Strictly, PCBD1 acts in BH4 regeneration/recycling rather than de novo
      synthesis, but GO groups the regeneration reactions under the
      tetrahydrobiopterin biosynthetic process node, and this is the accepted
      community annotation for the pterin-4-alpha-carbinolamine dehydratase
      family. UniProt annotates PCBD1 as involved in tetrahydrobiopterin
      biosynthesis. Retained as a core process (see core_functions), keeping in
      mind it reflects the recycling arm of the cycle.
    supported_by:
    - reference_id: PMID:24204001
      supporting_text: >-
        So far, HPABH4D caused by PCBD1 mutations has been considered a
        transient, benign condition, primarily related to impaired BH 4
        regeneration.
- term:
    id: GO:0008124
    label: 4-alpha-hydroxytetrahydrobiopterin dehydratase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic annotation to the core dehydratase activity, based on InterPro
      signatures and the RHEA/EC mapping (RHEA:11920, EC:4.2.1.96). Redundant
      with the IBA and ISS annotations to the same term.
    action: ACCEPT
    reason: >-
      Correct core molecular function, supported by multiple independent evidence
      lines. The with/from includes RHEA:11920 and EC:4.2.1.96, matching the
      UniProt catalytic activity statement.
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation inferred by inter-ontology link from the
      transcription coactivator activity (GO:0003713). This captures the DCoH
      coactivator role of PCBD1: it enhances HNF1A/HNF1B-dependent transcription.
    action: ACCEPT
    reason: >-
      The positive regulation of transcription process is well supported for the
      DCoH function. DCoH stabilizes the HNF1 dimer and enhances its
      transcriptional activity; PCBD1 costimulates the HNF1B-dependent FXYD2
      promoter. This is one of the two core functions and is retained as the
      process associated with the coactivator MF.
    supported_by:
    - reference_id: PMID:1763325
      supporting_text: >-
        did not change the DNA binding characteristics of HNF-1 alpha, but
        enhanced its transcriptional activity
    - reference_id: PMID:24204001
      supporting_text: >-
        Overexpression in a human kidney cell line showed that wild-type PCBD1
        binds HNF1B to costimulate the FXYD2 promoter
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: >-
      Generic protein binding from a large-scale human interactome mapping study.
      The recorded partners (FXR2/P51116, LNX1/Q8TBB1, NTAQ1/Q96HA8,
      GORASP2/Q9H8Y8) are high-throughput interactors of uncertain functional
      significance.
    action: KEEP_AS_NON_CORE
    reason: >-
      GO:0005515 protein binding is uninformative and does not identify a
      specific molecular function. It is not incorrect (PCBD1 does engage in
      protein-protein interactions), but the biologically meaningful interaction
      (with HNF1A/HNF1B, underlying the coactivator function) is better captured
      by the transcription coactivator activity term. Kept as non-core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20195357
  qualifier: enables
  review:
    summary: >-
      Generic protein binding from a proteome-scale study of interacting protein
      regions for transcription factor networks (partners APP/P05067,
      ACIN1/Q9UKV3).
    action: KEEP_AS_NON_CORE
    reason: >-
      Uninformative bare protein binding from a high-throughput screen. Not wrong
      but not a specific function; the functionally relevant HNF1 interaction is
      represented by the coactivator MF term.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20211142
  qualifier: enables
  review:
    summary: >-
      Generic protein binding from a combinatorial transcriptional regulation
      atlas (partners HNF1B/P35680, FXR2/P51116, PCBD2/Q9H0N5).
    action: KEEP_AS_NON_CORE
    reason: >-
      Bare protein binding; uninformative as a molecular function. Notably one
      partner here is HNF1B (P35680), which is the biologically important
      interaction underlying the coactivator role, better captured by
      GO:0003713. Kept as non-core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  qualifier: enables
  review:
    summary: >-
      Generic protein binding from a human liver protein interaction network
      study (partner PSMA1/P20823, a proteasome subunit).
    action: KEEP_AS_NON_CORE
    reason: >-
      Uninformative bare protein binding from a high-throughput dataset. The
      proteasome-subunit interaction may relate to the well-documented
      proteolytic turnover of destabilized PCBD1 disease variants, but as an
      annotation the term is non-specific. Kept as non-core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      Generic protein binding from a proteome-scale human interactome map
      (partners FXR2/P51116, TFF3/Q07654, LNX1/Q8TBB1).
    action: KEEP_AS_NON_CORE
    reason: >-
      Bare protein binding; non-specific and uninformative as a molecular
      function. Kept as non-core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26871637
  qualifier: enables
  review:
    summary: >-
      Generic protein binding from a study of interaction changes across
      alternative splicing (partner A0A0S2Z5X4, a ZNF688 isoform).
    action: KEEP_AS_NON_CORE
    reason: >-
      Uninformative bare protein binding from a high-throughput screen. Kept as
      non-core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29892012
  qualifier: enables
  review:
    summary: >-
      Generic protein binding from an interactome-perturbation study prioritizing
      damaging missense mutations (partner GORASP2/Q9H8Y8).
    action: KEEP_AS_NON_CORE
    reason: >-
      Bare protein binding; non-specific. Kept as non-core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: >-
      Generic protein binding from a study of interaction disruption by genetic
      variants (partners FXR2/P51116, GORASP2/Q9H8Y8).
    action: KEEP_AS_NON_CORE
    reason: >-
      Uninformative bare protein binding from a high-throughput dataset. Kept as
      non-core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Generic protein binding from the HuRI reference map of the human binary
      interactome (numerous partners, including HNF1B/P35680, SDCBP, PSMA1,
      TFF3, LNX1, NTAQ1, GORASP2, PICK1, KANK2).
    action: KEEP_AS_NON_CORE
    reason: >-
      Bare protein binding; uninformative as a molecular function, though it
      again includes the functionally central HNF1B (P35680) interaction that is
      better represented by the coactivator MF term. Kept as non-core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      Generic protein binding from the BioPlex dual proteome-scale interactome
      networks (partners HNF1B/P35680, PCBD2/Q9H0N5).
    action: KEEP_AS_NON_CORE
    reason: >-
      Uninformative bare protein binding from a high-throughput AP-MS dataset.
      Kept as non-core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35140242
  qualifier: enables
  review:
    summary: >-
      Generic protein binding from a systematic map of human transcription
      factor protein interaction networks (partners PSMA1/P20823, HNF1B/P35680).
    action: KEEP_AS_NON_CORE
    reason: >-
      Bare protein binding; non-specific. The HNF1B interaction is the meaningful
      one and is captured by GO:0003713. Kept as non-core.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: >-
      Self-interaction (PCBD1-PCBD1, P61457) detected in a large-scale human
      interactome screen, reflecting the homodimeric/homotetrameric assembly of
      PCBD1.
    action: KEEP_AS_NON_CORE
    reason: >-
      PCBD1 is a bona fide homotetramer/homodimer, so identical protein binding
      is a real and mechanistically relevant property (the tetramer competes with
      the PCBD1-HNF1 complex for the same interface). It is supportive rather than
      a standalone core function; kept as non-core.
    supported_by:
    - reference_id: PMID:24204001
      supporting_text: >-
        by assembling through the same interface, PCBD1 homotetramer and
        PCBD1–HNF1 complexes are mutually exclusive
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:20211142
  qualifier: enables
  review:
    summary: >-
      PCBD1 self-interaction detected in a combinatorial transcriptional
      regulation dataset, consistent with the homo-oligomeric assembly.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects the real homodimer/homotetramer of PCBD1. Supportive, kept as
      non-core.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  qualifier: enables
  review:
    summary: >-
      PCBD1 self-interaction detected using a next-generation sequencing
      interactome method, consistent with homo-oligomerization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects the real homo-oligomeric assembly of PCBD1. Supportive, kept as
      non-core.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      PCBD1 self-interaction from a proteome-scale interactome map, consistent
      with homodimer/homotetramer formation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects the genuine self-assembly of PCBD1. Supportive, kept as non-core.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      PCBD1 self-interaction in the HuRI binary interactome reference map,
      consistent with homo-oligomerization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects the real homodimer/homotetramer. Supportive, kept as non-core.
- term:
    id: GO:0004505
    label: phenylalanine 4-monooxygenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Electronic annotation transferred by Ensembl Compara (GO_REF:0000107) from
      the mouse ortholog Pcbd1 (with/from UniProtKB:P61458 /
      ENSMUSP00000020298). Phenylalanine 4-monooxygenase activity is the activity
      of phenylalanine hydroxylase (PAH), not PCBD1.
    action: REMOVE
    reason: >-
      This is a mis-annotation. GO:0004505 is defined as catalysis of
      L-phenylalanine + tetrahydrobiopterin + O2 = L-tyrosine +
      4-alpha-hydroxytetrahydrobiopterin, which is the reaction carried out by
      phenylalanine hydroxylase (PAH). PCBD1 does the opposite end of the cycle:
      it dehydrates the 4a-hydroxy-BH4 product of that hydroxylation
      (EC 4.2.1.96), regenerating BH4. PCBD1 has no phenylalanine hydroxylase
      catalytic machinery and is historically named phenylalanine
      hydroxylase-STIMULATING protein precisely because it accelerates cofactor
      turnover, not because it hydroxylates phenylalanine. This IEA is an
      over-propagated Compara transfer and should be removed; if not removed it
      is at minimum an over-annotation.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Electronic annotation transferred by Ensembl Compara from the mouse
      ortholog, capturing PCBD1 self-interaction (homo-oligomer).
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with the experimentally supported homodimer/homotetramer of
      PCBD1. Real but supportive; kept as non-core.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Direct immunofluorescence annotation (Human Protein Atlas, GO_REF:0000052)
      localizing PCBD1 to the nucleoplasm, consistent with the nuclear DCoH
      coactivator role.
    action: ACCEPT
    reason: >-
      Nuclear/nucleoplasmic localization is experimentally supported and required
      for the coactivator function; PCBD1 is recruited to the nucleus via HNF1B.
    supported_by:
    - reference_id: PMID:24204001
      supporting_text: >-
        We showed that Pcbd1 is localized in the nuclei of pancreatic cells.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Direct immunofluorescence annotation (Human Protein Atlas) localizing PCBD1
      to the cytosol, the site of the dehydratase reaction and of PCBD1
      homotetramers.
    action: ACCEPT
    reason: >-
      Cytosolic localization is experimentally established for PCBD1.
    supported_by:
    - reference_id: PMID:24204001
      supporting_text: >-
        Because Pcbd1 was present in the cytosol of renal cells
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:24204001
  qualifier: located_in
  review:
    summary: >-
      Experimental subcellular localization: PCBD1 localizes to the nucleus,
      where (recruited via HNF1B) it acts as an HNF1 coactivator.
    action: ACCEPT
    reason: >-
      Directly demonstrated experimentally. UniProt records Nucleus localization
      with the note that PCBD1 is recruited to the nucleus through interaction
      with HNF1B, from this study.
    supported_by:
    - reference_id: PMID:24204001
      supporting_text: >-
        the nuclear PCBD1 localization observed in the presence of wild-type
        HNF1B
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:24204001
  qualifier: located_in
  review:
    summary: >-
      Experimental subcellular localization: PCBD1 localizes to the cytoplasm,
      consistent with its cytosolic dehydratase activity and homotetramer pool.
    action: ACCEPT
    reason: >-
      Directly demonstrated experimentally; PCBD1 was present in the cytosol of
      renal cells and its cytosolic localization increased in the presence of
      HNF1B mutants.
    supported_by:
    - reference_id: PMID:24204001
      supporting_text: >-
        cytosolic localization of PCBD1 increased when coexpressed with HNF1B
        mutants
- term:
    id: GO:0008124
    label: 4-alpha-hydroxytetrahydrobiopterin dehydratase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Sequence-similarity annotation (ISS, manual transfer from an
      experimentally-verified ortholog, with/from UniProtKB:P61459) to the core
      dehydratase activity.
    action: ACCEPT
    reason: >-
      Correct core molecular function, redundant with the IBA and IEA annotations
      to the same term and consistent with the UniProt catalytic activity
      statement (EC 4.2.1.96).
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomic detection of PCBD1 in exosomes isolated from
      expressed prostatic secretions in urine.
    action: KEEP_AS_NON_CORE
    reason: >-
      Detection in exosome proteomes is a common finding for abundant cytosolic
      proteins and does not indicate a functional extracellular localization for
      PCBD1. Not part of its core enzymatic or coactivator functions; retained as
      non-core (localization observation only).
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomic detection of PCBD1 in urinary exosomes.
    action: KEEP_AS_NON_CORE
    reason: >-
      As above, exosomal detection reflects the abundance of this cytosolic
      protein rather than a dedicated extracellular function. Retained as
      non-core.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71146
  qualifier: located_in
  review:
    summary: >-
      Traceable author statement (Reactome) placing the PCBD1-catalyzed
      4a-hydroxy-BH4 dehydration reaction in the cytosol.
    action: ACCEPT
    reason: >-
      Correct cytosolic localization for the dehydratase reaction, part of the
      Reactome phenylalanine/BH4 metabolism pathway; consistent with
      experimental data.
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: TAS
  original_reference_id: PMID:1763325
  qualifier: enables
  review:
    summary: >-
      Traceable author statement capturing the DCoH function: PCBD1 is the
      dimerization cofactor of HNF1, stabilizing the HNF1 homodimer and enhancing
      its transcriptional activity without binding DNA itself. This is the second
      core function of the protein.
    action: ACCEPT
    reason: >-
      The DCoH/coactivator role is one of the two well-established functions of
      this bifunctional protein. DCoH selectively stabilizes HNF-1alpha dimers,
      forming a tetrameric complex that enhances transcription; DCoH does not
      confer activation to a heterologous GAL4 DNA-binding domain, consistent with
      a coactivator (not an autonomous activator) function. The HNF1B coactivator
      activity was later confirmed experimentally (PMID:24204001, FXYD2 promoter).
    supported_by:
    - reference_id: PMID:1763325
      supporting_text: >-
        A dimerization cofactor of HNF-1 alpha (DCoH) was identified that
        displayed a restricted tissue distribution and did not bind to DNA, but,
        rather, selectively stabilized HNF-1 alpha dimers.
    - reference_id: PMID:24204001
      supporting_text: >-
        our findings establish PCBD1 as a coactivator of the HNF1B-mediated
        transcription necessary for fine tuning FXYD2 transcription in the DCT
core_functions:
- description: >-
    Pterin-4-alpha-carbinolamine dehydratase (PCD/PHS) activity in the
    tetrahydrobiopterin (BH4) regeneration cycle: PCBD1 dehydrates
    (4aS,6R)-4a-hydroxy-tetrahydrobiopterin (the carbinolamine intermediate
    formed when BH4 serves as cofactor for aromatic amino acid hydroxylases such
    as phenylalanine hydroxylase) to quinonoid-6,7-dihydrobiopterin plus water,
    accelerating cofactor turnover and suppressing formation of 7-substituted
    (primapterin) pterins. Loss of this activity causes HPABH4D/primapterinuria.
  molecular_function:
    id: GO:0008124
    label: 4-alpha-hydroxytetrahydrobiopterin dehydratase activity
  directly_involved_in:
  - id: GO:0006729
    label: tetrahydrobiopterin biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:24204001
    supporting_text: >-
      So far, HPABH4D caused by PCBD1 mutations has been considered a transient,
      benign condition, primarily related to impaired BH 4 regeneration.
- description: >-
    Dimerization cofactor of HNF1 (DCoH) transcription coactivator activity:
    PCBD1 binds and stabilizes the homodimer of the homeodomain transcription
    factors HNF1A and HNF1B, forming a tetrameric complex that enhances
    HNF1-dependent transcription without binding DNA itself. Through HNF1B it
    costimulates target promoters such as FXYD2 (renal distal convoluted tubule),
    linking this moonlighting function to renal magnesium handling and to
    HNF1-associated MODY.
  molecular_function:
    id: GO:0003713
    label: transcription coactivator activity
  directly_involved_in:
  - id: GO:0045893
    label: positive regulation of DNA-templated transcription
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:1763325
    supporting_text: >-
      did not change the DNA binding characteristics of HNF-1 alpha, but enhanced
      its transcriptional activity
  - reference_id: PMID:24204001
    supporting_text: >-
      our findings establish PCBD1 as a coactivator of the HNF1B-mediated
      transcription necessary for fine tuning FXYD2 transcription in the DCT
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: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: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: >-
      The Ensembl Compara transfer from mouse Pcbd1 produced an incorrect
      GO:0004505 (phenylalanine 4-monooxygenase activity) annotation on PCBD1.
      That activity belongs to PAH, not PCBD1; this is an over-propagation
      artifact and the resulting annotation is recommended for removal.
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput interactome screen; contributes generic protein binding and
      self-interaction (identical protein binding) annotations. Does not establish
      a specific PCBD1 molecular function.
- id: PMID:1763325
  title: Characterization of a cofactor that regulates dimerization of a mammalian
    homeodomain protein.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Foundational DCoH paper (Mendel et al., Science 1991). Establishes PCBD1 as
      the dimerization cofactor of HNF-1alpha that stabilizes HNF1 dimers and
      enhances transcription without binding DNA. Abstract-only in cache
      (full_text_available false) but directly supports the coactivator core
      function.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput urinary exosome proteomics; source of the extracellular
      exosome localization annotation. Reflects abundance rather than a dedicated
      extracellular function.
- id: PMID:20195357
  title: A comprehensive resource of interacting protein regions for refining human
    transcription factor networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput interacting-regions dataset; contributes generic protein
      binding annotations only.
- id: PMID:20211142
  title: An atlas of combinatorial transcriptional regulation in mouse and man.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput interaction atlas; includes an HNF1B interaction but as a
      generic protein binding annotation.
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Methodological interactome dataset; source of an identical protein binding
      (self-interaction) annotation.
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput liver interactome; contributes a generic protein binding
      annotation (proteasome subunit partner).
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput exosome proteomics; source of an extracellular exosome
      localization annotation.
- id: PMID:24204001
  title: Mutations in PCBD1 cause hypomagnesemia and renal magnesium wasting.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Key functional paper (Ferre et al., JASN 2014; full text available).
      Experimentally establishes PCBD1 subcellular localization (cytoplasm and
      nucleus), the HNF1B interaction, and PCBD1 as a coactivator of
      HNF1B-mediated FXYD2 transcription in the renal DCT, with late complications
      (hypomagnesemia, MODY) in HPABH4D patients.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput interactome map; generic protein binding and
      self-interaction annotations.
- id: PMID:26871637
  title: Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput isoform interactome study; generic protein binding
      annotation.
- id: PMID:29892012
  title: An interactome perturbation framework prioritizes damaging missense mutations
    for developmental disorders.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput interactome perturbation study; generic protein binding
      annotation.
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the
    allele frequency spectrum in human populations.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput variant-interaction study; generic protein binding
      annotations.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI binary interactome reference map; generic protein binding (including
      HNF1B) and self-interaction annotations.
- 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 proteome-scale interactome networks; generic protein binding
      annotations (including HNF1B).
- id: PMID:35140242
  title: Human transcription factor protein interaction networks.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Systematic TF interaction network study; recovers the HNF1B interaction
      relevant to the coactivator role, but annotated only as generic protein
      binding.
- id: Reactome:R-HSA-71146
  title: 4a-hydroxytetrahydrobiopterin => q-dihydrobiopterin + H2O
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction for the PCBD1-catalyzed dehydration of 4a-hydroxy-BH4 to
      quinonoid-dihydrobiopterin in the cytosol; directly supports the core
      enzymatic function and its cytosolic localization.