PCBD1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005654 nucleoplasm	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:24204001 Furthermore, cytosolic localization of PCBD1 increased when coexpressed with HNF1B mutants.
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) annotation to the cytosol, the compartment where the dehydratase reaction of the BH4 cycle takes place and where PCBD1 homotetramers accumulate. 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. Supporting Evidence: PMID:24204001 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.
GO:0008124 4-alpha-hydroxytetrahydrobiopterin dehydratase activity	IBA GO_REF:0000033	ACCEPT	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. 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). Supporting Evidence: PMID:24204001 Mutations in PCBD1 have been shown to cause a transient and benign form of neonatal HPABH4D.
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (IEA) annotation to nucleus, redundant with and corroborated by the experimental EXP nuclear annotation from PMID:24204001. Reason: Nuclear localization is experimentally established for PCBD1 (recruited via HNF1B) and required for its coactivator function.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Electronic (IEA) annotation from the UniProt Subcellular Location mapping to cytoplasm, corroborated by experimental data. 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.
GO:0006571 L-tyrosine biosynthetic process	IEA GO_REF:0000108	REMOVE	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. 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.
GO:0006729 tetrahydrobiopterin biosynthetic process	IEA GO_REF:0000002	ACCEPT	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. 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. Supporting Evidence: PMID:24204001 So far, HPABH4D caused by PCBD1 mutations has been considered a transient, benign condition, primarily related to impaired BH 4 regeneration.
GO:0008124 4-alpha-hydroxytetrahydrobiopterin dehydratase activity	IEA GO_REF:0000120	ACCEPT	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. 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.
GO:0045893 positive regulation of DNA-templated transcription	IEA GO_REF:0000108	ACCEPT	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. 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. Supporting Evidence: PMID:1763325 did not change the DNA binding characteristics of HNF-1 alpha, but enhanced its transcriptional activity PMID:24204001 Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	KEEP AS NON CORE	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. 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.
GO:0005515 protein binding	IPI PMID:20195357 A comprehensive resource of interacting protein regions for ...	KEEP AS NON CORE	Summary: Generic protein binding from a proteome-scale study of interacting protein regions for transcription factor networks (partners APP/P05067, ACIN1/Q9UKV3). 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.
GO:0005515 protein binding	IPI PMID:20211142 An atlas of combinatorial transcriptional regulation in mous...	KEEP AS NON CORE	Summary: Generic protein binding from a combinatorial transcriptional regulation atlas (partners HNF1B/P35680, FXR2/P51116, PCBD2/Q9H0N5). 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.
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	KEEP AS NON CORE	Summary: Generic protein binding from a human liver protein interaction network study (partner PSMA1/P20823, a proteasome subunit). 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.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: Generic protein binding from a proteome-scale human interactome map (partners FXR2/P51116, TFF3/Q07654, LNX1/Q8TBB1). Reason: Bare protein binding; non-specific and uninformative as a molecular function. Kept as non-core.
GO:0005515 protein binding	IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ...	KEEP AS NON CORE	Summary: Generic protein binding from a study of interaction changes across alternative splicing (partner A0A0S2Z5X4, a ZNF688 isoform). Reason: Uninformative bare protein binding from a high-throughput screen. Kept as non-core.
GO:0005515 protein binding	IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m...	KEEP AS NON CORE	Summary: Generic protein binding from an interactome-perturbation study prioritizing damaging missense mutations (partner GORASP2/Q9H8Y8). Reason: Bare protein binding; non-specific. Kept as non-core.
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	KEEP AS NON CORE	Summary: Generic protein binding from a study of interaction disruption by genetic variants (partners FXR2/P51116, GORASP2/Q9H8Y8). Reason: Uninformative bare protein binding from a high-throughput dataset. Kept as non-core.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	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). 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.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: Generic protein binding from the BioPlex dual proteome-scale interactome networks (partners HNF1B/P35680, PCBD2/Q9H0N5). Reason: Uninformative bare protein binding from a high-throughput AP-MS dataset. Kept as non-core.
GO:0005515 protein binding	IPI PMID:35140242 Human transcription factor protein interaction networks.	KEEP AS NON CORE	Summary: Generic protein binding from a systematic map of human transcription factor protein interaction networks (partners PSMA1/P20823, HNF1B/P35680). Reason: Bare protein binding; non-specific. The HNF1B interaction is the meaningful one and is captured by GO:0003713. Kept as non-core.
GO:0042802 identical protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	KEEP AS NON CORE	Summary: Self-interaction (PCBD1-PCBD1, P61457) detected in a large-scale human interactome screen, reflecting the homodimeric/homotetrameric assembly of PCBD1. 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. Supporting Evidence: PMID:24204001 by assembling through the same interface, PCBD1 homotetramer and PCBD1–HNF1 complexes are mutually exclusive
GO:0042802 identical protein binding	IPI PMID:20211142 An atlas of combinatorial transcriptional regulation in mous...	KEEP AS NON CORE	Summary: PCBD1 self-interaction detected in a combinatorial transcriptional regulation dataset, consistent with the homo-oligomeric assembly. Reason: Reflects the real homodimer/homotetramer of PCBD1. Supportive, kept as non-core.
GO:0042802 identical protein binding	IPI PMID:21516116 Next-generation sequencing to generate interactome datasets.	KEEP AS NON CORE	Summary: PCBD1 self-interaction detected using a next-generation sequencing interactome method, consistent with homo-oligomerization. Reason: Reflects the real homo-oligomeric assembly of PCBD1. Supportive, kept as non-core.
GO:0042802 identical protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: PCBD1 self-interaction from a proteome-scale interactome map, consistent with homodimer/homotetramer formation. Reason: Reflects the genuine self-assembly of PCBD1. Supportive, kept as non-core.
GO:0042802 identical protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: PCBD1 self-interaction in the HuRI binary interactome reference map, consistent with homo-oligomerization. Reason: Reflects the real homodimer/homotetramer. Supportive, kept as non-core.
GO:0004505 phenylalanine 4-monooxygenase activity	IEA GO_REF:0000107	REMOVE	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. 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.
GO:0042802 identical protein binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Electronic annotation transferred by Ensembl Compara from the mouse ortholog, capturing PCBD1 self-interaction (homo-oligomer). Reason: Consistent with the experimentally supported homodimer/homotetramer of PCBD1. Real but supportive; kept as non-core.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: Direct immunofluorescence annotation (Human Protein Atlas, GO_REF:0000052) localizing PCBD1 to the nucleoplasm, consistent with the nuclear DCoH coactivator role. Reason: Nuclear/nucleoplasmic localization is experimentally supported and required for the coactivator function; PCBD1 is recruited to the nucleus via HNF1B. Supporting Evidence: PMID:24204001 We showed that Pcbd1 is localized in the nuclei of pancreatic cells.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Direct immunofluorescence annotation (Human Protein Atlas) localizing PCBD1 to the cytosol, the site of the dehydratase reaction and of PCBD1 homotetramers. Reason: Cytosolic localization is experimentally established for PCBD1. Supporting Evidence: PMID:24204001 Because Pcbd1 was present in the cytosol of renal cells
GO:0005634 nucleus	EXP PMID:24204001 Mutations in PCBD1 cause hypomagnesemia and renal magnesium ...	ACCEPT	Summary: Experimental subcellular localization: PCBD1 localizes to the nucleus, where (recruited via HNF1B) it acts as an HNF1 coactivator. 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. Supporting Evidence: PMID:24204001 the nuclear PCBD1 localization observed in the presence of wild-type HNF1B
GO:0005737 cytoplasm	EXP PMID:24204001 Mutations in PCBD1 cause hypomagnesemia and renal magnesium ...	ACCEPT	Summary: Experimental subcellular localization: PCBD1 localizes to the cytoplasm, consistent with its cytosolic dehydratase activity and homotetramer pool. Reason: Directly demonstrated experimentally; PCBD1 was present in the cytosol of renal cells and its cytosolic localization increased in the presence of HNF1B mutants. Supporting Evidence: PMID:24204001 cytosolic localization of PCBD1 increased when coexpressed with HNF1B mutants
GO:0008124 4-alpha-hydroxytetrahydrobiopterin dehydratase activity	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity annotation (ISS, manual transfer from an experimentally-verified ortholog, with/from UniProtKB:P61459) to the core dehydratase activity. 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).
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	KEEP AS NON CORE	Summary: High-throughput proteomic detection of PCBD1 in exosomes isolated from expressed prostatic secretions in urine. 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).
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: High-throughput proteomic detection of PCBD1 in urinary exosomes. Reason: As above, exosomal detection reflects the abundance of this cytosolic protein rather than a dedicated extracellular function. Retained as non-core.
GO:0005829 cytosol	TAS Reactome:R-HSA-71146	ACCEPT	Summary: Traceable author statement (Reactome) placing the PCBD1-catalyzed 4a-hydroxy-BH4 dehydration reaction in the cytosol. Reason: Correct cytosolic localization for the dehydratase reaction, part of the Reactome phenylalanine/BH4 metabolism pathway; consistent with experimental data.
GO:0003713 transcription coactivator activity	TAS PMID:1763325 Characterization of a cofactor that regulates dimerization o...	ACCEPT	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. 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). Supporting Evidence: PMID:1763325 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. PMID:24204001 our findings establish PCBD1 as a coactivator of the HNF1B-mediated transcription necessary for fine tuning FXYD2 transcription in the DCT

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

📚 Additional Documentation

Notes

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