Pcbd1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0003713 transcription coactivator activity	ISO PMID:1763325 Characterization of a cofactor that regulates dimerization o...	ACCEPT	Summary: The DCoH half of this moonlighting protein. Pcbd1 binds Hnf1a, stabilises its homodimer, and increases HNF1-dependent transcription without binding DNA or changing Hnf1a DNA-binding affinity. This is a core function, distinct from the dehydratase activity. Reason: Mendel et al. define the activity precisely as that of a coactivator: DCoH does not contact DNA, it stabilises the HNF1-alpha dimer, and the resulting tetramer has enhanced transcriptional output. The specificity control in the same paper - DCoH cannot activate transcription when tethered via the GAL4 DNA-binding domain - shows this is an HNF1-directed cofactor activity rather than a transferable activation domain, which is exactly what GO:0003713 describes. Recorded as ISO from rat Pcbd1 (UniProtKB:P61459); the mouse protein is the one cloned in this paper, so the evidence may in fact be direct (raised in suggested_questions), but the term is right either way. 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:1763325 did not change the DNA binding characteristics of HNF-1 alpha, but enhanced its transcriptional activity file:mouse/Pcbd1/Pcbd1-uniprot.txt Coactivator for HNF1A-dependent transcription.
GO:0004505 phenylalanine 4-monooxygenase activity	IDA PMID:15182178 Biochemical and structural basis for partially redundant enz...	MODIFY	Summary: This is the annotation that geneontology/go-annotation#6591 asks to correct. GO:0004505 is the activity of phenylalanine hydroxylase (Pah), the enzyme one step upstream of Pcbd1 in the BH4 cycle. The assay in PMID:15182178 measured pterin-4-alpha-carbinolamine dehydratase activity, which is GO:0008124. Reason: The two terms name consecutive steps of one cycle, which is why they get interchanged. GO:0004505 is "Catalysis of the reaction: L-phenylalanine + tetrahydrobiopterin + O2 = L-tyrosine + 4-alpha-hydroxytetrahydrobiopterin" (synonyms: phenylalanine hydroxylase activity, PAH activity). Pcbd1 catalyses the next step instead: it dehydrates that 4a-hydroxy-BH4 product to quinonoid-BH2, which is GO:0008124, whose own synonym list contains "pterin-4-alpha-carbinolamine dehydratase activity" verbatim. The error almost certainly comes from the protein's historical name, phenylalanine hydroxylase-STIMULATING protein: Pcbd1 stimulates Pah by accelerating cofactor turnover, it does not hydroxylate phenylalanine. UniProt independently assigns EC 4.2.1.96 and the Lyase keyword to this entry, which is incompatible with a monooxygenase (EC 1.14.16.1). The experiment, the evidence code and the reference are all sound - only the term is wrong - so this is a MODIFY that keeps IDA and PMID:15182178 and swaps the term. Proposed replacements: 4-alpha-hydroxytetrahydrobiopterin dehydratase activity Supporting Evidence: PMID:15182178 Like DCoH, DCoH2 forms a tetramer, displays pterin-4alpha-carbinolamine dehydratase activity, and binds HNF1alpha in vivo and in vitro. file:mouse/Pcbd1/Pcbd1-uniprot.txt AltName: Full=Phenylalanine hydroxylase-stimulating protein file:mouse/Pcbd1/Pcbd1-uniprot.txt EC=4.2.1.96
GO:0004505 phenylalanine 4-monooxygenase activity	IEA GO_REF:0000117	REMOVE	Summary: An ARBA machine-learning rule independently assigning phenylalanine 4-monooxygenase activity. Same wrong term as the IDA above, but reached by a different route, so correcting the IDA will not clear it. Reason: Pcbd1 has no monooxygenase chemistry: no iron centre, no pterin-dependent hydroxylase domain, and a UniProt EC assignment of 4.2.1.96 (a hydro-lyase) with the Lyase keyword. ARBA00029278 appears to have learned an association from the BH4/phenylalanine-hydroxylation context that surrounds the PCD family rather than from the family's own catalytic signature; it fires on both mouse paralogs. This is an electronic inference contradicted by the curated EC and reaction, and should be removed independently of the MGI correction requested in geneontology/go-annotation#6591. Supporting Evidence: file:mouse/Pcbd1/Pcbd1-uniprot.txt Direct protein sequencing; Lyase;
GO:0005515 protein binding	IPI PMID:15182178 Biochemical and structural basis for partially redundant enz...	MODIFY	Summary: Interaction with PR:P22361, which is mouse Hnf1a. The binding partner is the informative part and the bare protein binding term discards it. Reason: Per project curation guidelines, GO:0005515 protein binding carries no functional information and should be replaced by a term that states what is bound. The partner here is Hnf1a, a sequence-specific DNA-binding transcription factor, so GO:0140297 ("Binding to a DNA-binding transcription factor, a protein that interacts with a specific DNA sequence ... to modulate transcription") captures the experiment exactly. This is the binding event that underlies the GO:0003713 coactivator activity above; the two are complementary, with GO:0140297 recording the molecular recognition and GO:0003713 its functional consequence. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:1763325 The formation of a stable tetrameric DCoH-HNF-1 alpha complex, which required the dimerization domain of HNF-1 alpha file:mouse/Pcbd1/Pcbd1-uniprot.txt Heterotetramer with HNF1A
GO:0005515 protein binding	IPI PMID:15182178 Biochemical and structural basis for partially redundant enz...	UNDECIDED	Summary: Interaction with PR:Q9CZL5, the paralog Pcbd2 (DCoH2). PMID:15182178 reports that the DCoH2 tetramer disproportionates, which is the basis for mixed DCoH/DCoH2 oligomers; this is a real but supportive observation. Reason: A bare protein-binding row should be replaced by a term naming what is bound, and the obvious candidate here is GO:0046982 protein heterodimerization activity ("Binding to a nonidentical protein to form a heterodimer"), since Pcbd2 is a paralog rather than the same protein and so GO:0042802 cannot apply. I cannot justify that replacement from what I can see. The cached record for PMID:15182178 is abstract-only, and the abstract describes DCoH2 disproportionating and forming a 2:2 complex with HNF1 - it says nothing about a mixed DCoH/DCoH2 species. The MGI curator read the full text and recorded a Pcbd1-Pcbd2 interaction, so the interaction itself is not in doubt; what I cannot determine is whether the data show a discrete heterodimer, a mixed tetramer, or subunit exchange between separately assembled tetramers, and those map to different terms. UNDECIDED pending the full text. If it shows a defined mixed species, MODIFY to GO:0046982; if it shows subunit exchange within the oligomer population, the useful representation is a complex term or a GO-CAM rather than a molecular function row, which is raised in suggested_questions. Do not read this as doubt about the interaction. Supporting Evidence: PMID:15182178 In contrast to the hyperstable DCoH tetramer, DCoH2 readily disproportionates and forms a 2:2 complex with HNF1 in vitro.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: Nucleus from the UniProt SubCell keyword mapping (SL-0191). Consistent with the DCoH coactivator function, which requires the protein to reach HNF1 target promoters. Reason: UniProt's SUBCELLULAR LOCATION for this entry lists both Cytoplasm and Nucleus, with the note that the protein is recruited to the nucleus through its interaction with HNF1B. The keyword mapping faithfully reproduces a curated statement, and nuclear residence is required for the coactivator half of the protein's function. Redundant with the several ISO/ISS nucleus rows below, which is pipeline duplication rather than an error. Supporting Evidence: file:mouse/Pcbd1/Pcbd1-uniprot.txt Note=Recruited to the nucleus through
GO:0005634 nucleus	IPI PMID:15182178 Biochemical and structural basis for partially redundant enz...	ACCEPT	Summary: Nuclear localization inferred from the in vivo interaction with Hnf1a (PR:P22361), a nuclear transcription factor. Reason: The abstract states the HNF1alpha interaction was demonstrated in vivo as well as in vitro, so co-residence with a nuclear transcription factor is a reasonable basis for the compartment. This is weaker evidence than a direct imaging or fractionation experiment, but it is not in tension with any other evidence and the compartment is independently supported by UniProt and by the human ortholog. Supporting Evidence: PMID:15182178 binds HNF1alpha in vivo and in vitro
GO:0005634 nucleus	ISO GO_REF:0000096	ACCEPT	Summary: Nucleus transferred from the experimentally annotated rat ortholog (RGD:3263). Reason: Rat and mouse Pcbd1 are close orthologs with the same two functions, and the compartment is independently supported on the mouse entry by UniProt and by the in vivo Hnf1a interaction. One of several redundant nucleus rows; correct, not informative beyond the others.
GO:0005634 nucleus	ISO GO_REF:0000119	ACCEPT	Summary: Nucleus transferred from the experimentally annotated human ortholog PCBD1 (P61457). Reason: Human PCBD1 has direct immunofluorescence and interaction evidence for nuclear localization, reviewed in genes/human/PCBD1. The mouse-human orthology is unambiguous and the function requiring the nucleus (HNF1 coactivation) is shared. Redundant with the other nucleus rows.
GO:0005634 nucleus	ISO PMID:1763325 Characterization of a cofactor that regulates dimerization o...	ACCEPT	Summary: Nucleus transferred from rat Pcbd1 (P61459) on the basis of the original DCoH characterization. Reason: Mendel et al. characterized DCoH as a nuclear cofactor forming transcriptionally active tetrameric complexes with HNF-1 alpha, which places it in the nucleus. Correct but redundant with the preceding nucleus annotations. Supporting Evidence: PMID:1763325 These results indicate that DCoH regulates formation of transcriptionally active tetrameric complexes
GO:0005634 nucleus	ISS GO_REF:0000024	ACCEPT	Summary: Nucleus by curator-judged sequence similarity to rat Pcbd1. Reason: Same compartment, same source organism as the ISO row above, reached by a different UniProt pipeline. Not wrong; the sixth nucleus annotation on this gene product adds nothing.
GO:0005654 nucleoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic annotation placing Pcbd1 activity in the nucleoplasm, from PANTHER node PTN002650414. The is_active_in qualifier correctly asserts this is where a function is executed, not merely where the protein is found. Reason: The cached PAINT table for PTHR12599 contains a non-negated IBD for GO:0005654 at PTN002650414, placed at taxon:117571 (Euteleostomi) and seeded by UniProtKB:P61457 (human PCBD1). Mouse Pcbd1 descends from that node, so the propagation is sound. A single well-characterized donor is not a weakness, and human PCBD1 appearing in WITH alongside the node is the expected marker of experimental grounding. The nucleoplasm is where the DCoH coactivator function operates. Supporting Evidence: file:mouse/Pcbd1/Pcbd1-uniprot.txt Coactivator for HNF1A-dependent transcription.
GO:0005654 nucleoplasm	IEA GO_REF:0000107	ACCEPT	Summary: Nucleoplasm transferred from human PCBD1 by Ensembl Compara. Reason: The human source annotation is a direct immunofluorescence observation, and the orthology call is unambiguous. Note that this same Compara pipeline is responsible for propagating the erroneous GO:0004505 from mouse to human; the pipeline is not unreliable in general, but its outputs inherit whatever is wrong at the source.
GO:0005654 nucleoplasm	ISO GO_REF:0000119	ACCEPT	Summary: Nucleoplasm transferred from human PCBD1 by the mouse-human ortholog pipeline. Reason: Same claim and same source as the Compara row above, via a second pipeline. Correct and redundant.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Cytoplasm from the UniProt SubCell keyword mapping (SL-0086), reproducing the curated Cytoplasm location. Reason: Correct but less informative than the cytosol annotations below, which name the actual compartment where the dehydratase reaction occurs. Keeping the parent term alongside its child is ordinary GOA redundancy rather than an over-annotation, so ACCEPT rather than MODIFY. Supporting Evidence: file:mouse/Pcbd1/Pcbd1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm
GO:0005737 cytoplasm	ISO GO_REF:0000096	ACCEPT	Summary: Cytoplasm transferred from the rat ortholog. Reason: Correct compartment, redundant with the other cytoplasm and cytosol rows.
GO:0005737 cytoplasm	ISO GO_REF:0000119	ACCEPT	Summary: Cytoplasm transferred from human PCBD1. Reason: Cytosolic localization of human PCBD1 is directly observed in renal cells (PMID:24204001, reviewed in genes/human/PCBD1). Correct but redundant.
GO:0005737 cytoplasm	ISS GO_REF:0000024	ACCEPT	Summary: Cytoplasm by curator-judged sequence similarity to rat Pcbd1. Reason: Fourth cytoplasm annotation; correct, adds nothing beyond the others.
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic annotation placing Pcbd1 activity in the cytosol. This is the compartment where the enzymatic half of the protein works. Reason: The cached PTHR12599 PAINT table has a non-negated GO:0005829 IBD at PTN002650414, at the Euteleostomi node, seeded by human PCBD1. The placement makes biological sense: the aromatic amino acid hydroxylases that generate 4a-hydroxy-BH4 are cytosolic, so the dehydratase must act there for the BH4 cycle to turn over. is_active_in is the right qualifier for the compartment of catalysis.
GO:0005829 cytosol	IEA GO_REF:0000107	ACCEPT	Summary: Cytosol transferred from human PCBD1 by Ensembl Compara. Reason: Human PCBD1 cytosolic localization is directly observed; the transfer is correct. Redundant with the IBA and ISO cytosol rows.
GO:0005829 cytosol	ISO GO_REF:0000119	ACCEPT	Summary: Cytosol transferred from human PCBD1 by the mouse-human ortholog pipeline. Reason: Correct and redundant with the two preceding cytosol annotations.
GO:0006571 L-tyrosine biosynthetic process	IEA GO_REF:0000108	REMOVE	Summary: An inter-ontology logical inference whose WITH field names GO:0004505 as its source. It is a mechanical consequence of the mis-annotated molecular function and inherits its error. Reason: The inference rule is sound - a phenylalanine 4-monooxygenase does participate in tyrosine biosynthesis - but its premise is false for this gene. Tyrosine is made by Pah; Pcbd1 acts after the hydroxylation, on the spent cofactor. Under the project rule that a gene product is involved_in a process only if it performs some of the work of that process, Pcbd1 contributes nothing to tyrosine formation: the carbon skeleton of tyrosine is never in its hands. Note the comparator - Qdpr, which performs the other regeneration step, is likewise not a tyrosine biosynthetic enzyme. This annotation should disappear once GO:0004505 is corrected; if the MF is instead left in place, this row still needs removing separately because the ARBA-sourced GO:0004505 would keep regenerating it.
GO:0006729 tetrahydrobiopterin biosynthetic process	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO annotation from the pterin dehydratase domain signatures. Pcbd1 regenerates BH4 from the 4a-hydroxy-BH4 carbinolamine produced during aromatic amino acid hydroxylation. Reason: Strictly, Pcbd1 acts in BH4 regeneration/recycling rather than in de novo synthesis from GTP (the Gch1/Pts/Spr route), so the term is broader than the precise role. But Pcbd1 does perform a chemical step whose product feeds back into the BH4 pool, so it is a genuine participant rather than a substrate or a mere requirement, and GO has no separate regeneration child to move to. The InterPro signatures IPR001533/IPR036428 are the correct family signatures for this protein and the mapping is appropriate at the family level. Accepted as a core process. Supporting Evidence: file:mouse/Pcbd1/Pcbd1-uniprot.txt Involved in tetrahydrobiopterin biosynthesis.
GO:0008124 4-alpha-hydroxytetrahydrobiopterin dehydratase activity	IBA GO_REF:0000033	ACCEPT	Summary: The correct molecular function, propagated phylogenetically. This is the term that geneontology/go-annotation#6591 asks MGI to use for its experimental annotation. Reason: The cached PTHR12599 PAINT table shows a non-negated GO:0008124 IBD at PTN002650414, placed at taxon:117571 (Euteleostomi) and seeded by RGD:3263 (rat Pcbd1), which has the experimental annotation. Mouse Pcbd1 is inside that clade, shares the complete catalytic signature, and has no evidence of functional divergence or loss. A single-MOD donor list is not a defect. The term matches UniProt's own EC 4.2.1.96 and RHEA:11920 assignment for the mouse entry. Supporting Evidence: file:mouse/Pcbd1/Pcbd1-uniprot.txt EC=4.2.1.96
GO:0008124 4-alpha-hydroxytetrahydrobiopterin dehydratase activity	IEA GO_REF:0000120	ACCEPT	Summary: The same correct function from the combined automated pipeline, cross-referenced to RHEA:11920 and EC 4.2.1.96. Reason: Four independent lines of support converge here: the InterPro family signatures, the RHEA reaction, the EC number, and UniProt's curated CATALYTIC ACTIVITY block for this entry. This row is also the direct refutation of the GO:0004505 annotations on the same gene product - the two EC classes (4.2.1.- hydro-lyase versus 1.14.16.- monooxygenase) are mutually exclusive.
GO:0008124 4-alpha-hydroxytetrahydrobiopterin dehydratase activity	ISO GO_REF:0000096	ACCEPT	Summary: Dehydratase activity transferred from the experimentally annotated rat ortholog. Reason: Rat Pcbd1 is the classic biochemical source for this activity and the orthology is unambiguous. Redundant with the IBA, IEA and ISS rows for the same term, and - once the MGI IDA is corrected per geneontology/go-annotation#6591 - with a direct mouse experimental annotation as well.
GO:0008124 4-alpha-hydroxytetrahydrobiopterin dehydratase activity	ISS GO_REF:0000024	ACCEPT	Summary: Dehydratase activity by curator-judged sequence similarity to rat Pcbd1. Reason: This is the row UniProt's own EC assignment rests on, cited there as ECO:0000250\|UniProtKB:P61459. Correct; redundant with the three other GO:0008124 annotations.
GO:0042802 identical protein binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Self-interaction transferred from human PCBD1 by Ensembl Compara. Reason: Pcbd1 is a genuine homodimer and homotetramer, so the term is factually right. Self-association is a structural property that enables both functions rather than a function in its own right - the catalytic site of PCD is formed at a subunit interface and the DCoH-HNF1 tetramer is a dimer of dimers - so it is kept as supportive, not core. Supporting Evidence: file:mouse/Pcbd1/Pcbd1-uniprot.txt Homotetramer and homodimer.
GO:0042802 identical protein binding	IPI PMID:15182178 Biochemical and structural basis for partially redundant enz...	KEEP AS NON CORE	Summary: Direct self-interaction evidence from PMID:15182178, which reports the DCoH tetramer as hyperstable. Reason: The strongest of the three identical-protein-binding rows, being experimental and on the mouse protein itself. Still a structural property rather than a core activity. Supporting Evidence: PMID:15182178 In contrast to the hyperstable DCoH tetramer, DCoH2 readily disproportionates and forms a 2:2 complex with HNF1 in vitro.
GO:0042802 identical protein binding	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Self-interaction transferred from human PCBD1. Reason: Redundant with the direct mouse IPI evidence for the same term, which is stronger. Correct, non-core.
GO:0045893 positive regulation of DNA-templated transcription	ISO PMID:1763325 Characterization of a cofactor that regulates dimerization o...	ACCEPT	Summary: The biological process matching the DCoH coactivator activity: Pcbd1 increases HNF1-dependent transcription by stabilising the active HNF1 tetramer. Reason: Pcbd1 performs part of the work of this process - it is a physical component of the transcriptionally active tetramer at HNF1 target promoters, not merely an upstream requirement - so the process annotation is appropriate and core. The term is right; the qualifier is weaker than the evidence warrants. acts_upstream_of_or_within is the appropriate hedge when it is unclear whether the gene product is part of the process or acts before it, but Mendel et al. show DCoH inside the complex that does the activating, so involved_in would be better supported. Flagged rather than actioned, since a qualifier change is a curator call and not a term replacement. Supporting Evidence: PMID:1763325 These results indicate that DCoH regulates formation of transcriptionally active tetrameric complexes PMID:1763325 did not change the DNA binding characteristics of HNF-1 alpha, but enhanced its transcriptional activity

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