id: A0A8C4LTV9 gene_symbol: PDIA4 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9793 label: Equus asinus description: 'PDIA4 (ERp72) is an endoplasmic reticulum luminal oxidoreductase of the protein disulfide isomerase (PDI) family (PANTHER subfamily PTHR18929:SF210, protein disulfide-isomerase A4). Mammalian PDIA4 has an N-terminal signal peptide, an acidic N-terminal stretch, three catalytic thioredoxin-like a-type domains carrying CGHC redox-active sites, two non-catalytic b-type domains, and a C-terminal KDEL-type ER retrieval signal. It catalyses thiol-disulfide oxidation, reduction and isomerization of client proteins during oxidative folding in the ER, and works within a large ER chaperone network with HSPA5 (BiP), HSP90B1 (GRP94), PPIB (cyclophilin B), PDIA6 and other folding factors that binds unfolded secretory proteins. It is an ER stress-inducible protein, and small amounts are released and found at the cell surface, for example on activated platelets. The donkey UniProt entry A0A8C4LTV9 (1197 aa) is a merged gene model: residues ~581-1197 are the PDIA4 product (90% identical to human PDIA4 over residues 31-645, all three CGHC sites conserved, C-terminal REEL), but they are preceded by a KRAB domain and ten C2H2 zinc fingers that are most similar to human ZNF786, the gene immediately upstream of PDIA4 on the same strand in human, and the PDIA4 signal peptide is missing. The zinc-finger part is not PDIA4 biology.' existing_annotations: - term: id: GO:0003756 label: protein disulfide isomerase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables supporting_entities: - InterPro:IPR005788 - InterPro:IPR005792 - EC:5.3.4.1 - PANTHER:PTN008566466 review: summary: Protein disulfide isomerase activity (EC 5.3.4.1 / UniRule, combined IEA). action: ACCEPT reason: The PDIA4 portion of the donkey entry sits in PANTHER subfamily PTHR18929:SF210 (PDIA4) and retains all three CGHC redox-active sites of human ERp72. PAINT curators placed protein disulfide isomerase activity at the PDI family root node PTN000432607, from which PDIA4 orthologs inherit it, and human ERp72 has measured peptide thiol-disulfide oxidase activity comparable to PDI. This is the core catalytic function of PDIA4. supported_by: - reference_id: PMID:16677074 supporting_text: we have recombinantly expressed and purified six members of the family, PDI, PDIp, ERp57, ERp72, P5, and PDIr from a single organism, human. An examination of the pH-dependence and nature of the rate limiting step for the peptide thiol-disulfide oxidase activity of these enzymes reveals that, with the exception of PDIr, they are all remarkably similar. - reference_id: file:EQUAS/PDIA4/PDIA4-bioinformatics/RESULTS.md supporting_text: 'DISULFID Redox-active: human [91, 94] CC -> donkey [643, 646] CC' - reference_id: file:EQUAS/PDIA4/PDIA4-uniprot.txt record_section: ["DR:PANTHER"] supporting_text: PANTHER; PTHR18929:SF210; PROTEIN DISULFIDE-ISOMERASE A4; 1. - reference_id: file:EQUAS/PDIA4/PDIA4-bioinformatics/RESULTS.md supporting_text: 'DISULFID Redox-active: human [555, 558] CC -> donkey [1107, 1110] CC' - reference_id: file:EQUAS/PDIA4/PDIA4-uniprot.txt record_section: ["CC:SIMILARITY"] supporting_text: 'SIMILARITY: Belongs to the protein disulfide isomerase family.' - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in supporting_entities: - ARBA:ARBA00026330 - UniProtKB-SubCell:SL-0191 review: summary: Nucleus (UniProt subcellular location rule, combined IEA). action: REMOVE reason: PDIA4 is an ER luminal enzyme with no nuclear function. The nuclear location in this entry comes from the KRAB-C2H2 zinc-finger segment at its N-terminus, which matches human ZNF786 (64% identity) rather than PDIA4; in human, ZNF786 lies immediately upstream of PDIA4 on the same strand, and the donkey annotation has no separate ZNF786 gene, so the segment reflects a merged ZNF786-PDIA4 gene model. The term does not describe PDIA4 biology. supported_by: - reference_id: file:EQUAS/PDIA4/PDIA4-uniprot.txt record_section: ["DR:InterPro"] supporting_text: InterPro; IPR001909; KRAB. - reference_id: file:EQUAS/PDIA4/PDIA4-bioinformatics/RESULTS.md supporting_text: 'Donkey A0A8C4LTV9 (1197 aa) aligned globally to human P13667 (645 aa): 88.37% identity over 645 paired residues; paired coverage 100.0% of human and 53.88% of donkey.' - reference_id: file:EQUAS/PDIA4/PDIA4-bioinformatics/human-P13667-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen {ECO:0000269|PubMed:12643545}.' - reference_id: file:EQUAS/PDIA4/PDIA4-bioinformatics/RESULTS-rereview.md supporting_text: 'N-terminal segment vs human ZNF786 (Q8N393, 782 aa): 64.2% identity over 565 paired residues; donkey 1-580, human 1-649' source_defects: - defect_type: OTHER resource: OTHER slot: DB_Object_ID requested_change: CHECK asserted_value: UniProtKB:A0A8C4LTV9 cause: SEQUENCE_MISMAPPING confidence: PROBABLE explanation: 'Resource: Ensembl gene build (propagated into UniProt TrEMBL). The Ensembl donkey gene model ENSEASG00005009014 (PDIA4, transcript ENSEAST00005014006) joins a KRAB-C2H2 zinc-finger segment most similar to human ZNF786 (residues 1-580) to the PDIA4 coding sequence and omits the PDIA4 signal peptide. In human, ZNF786 is a separate gene immediately upstream of PDIA4, and the donkey annotation lacks a ZNF786 gene. Electronic annotations derived from the zinc-finger segment (nucleus, regulation of DNA-templated transcription) are therefore attached to PDIA4 in error; the gene model should be split.' supported_by: - reference_id: file:EQUAS/PDIA4/PDIA4-bioinformatics/RESULTS-rereview.md supporting_text: ENSEASG00005035571 ZNF425 1004371-1014880 strand 1 - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in supporting_entities: - ARBA:ARBA00028672 - PANTHER:PTN008566466 review: summary: Endoplasmic reticulum. action: TOO_GENERAL reason: Correct (it is the PAINT IBD placed at the PDI family root node PTN000432607), but the accepted, more specific location endoplasmic reticulum lumen entails it. supported_by: - reference_id: file:EQUAS/PDIA4/PDIA4-bioinformatics/human-P13667-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen {ECO:0000269|PubMed:12643545}.' - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0096 review: summary: Endoplasmic reticulum lumen. action: ACCEPT reason: Human PDIA4 is an ER luminal resident retained by its C-terminal KDEL-type signal; the donkey PDIA4 portion ends with the equivalent REEL motif. The donkey gene model lacks the signal peptide needed for ER entry, which is attributed to the gene-model fusion, not to the biology of donkey PDIA4. supported_by: - reference_id: file:EQUAS/PDIA4/PDIA4-bioinformatics/human-P13667-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen {ECO:0000269|PubMed:12643545}.' - reference_id: file:EQUAS/PDIA4/PDIA4-bioinformatics/RESULTS.md supporting_text: 'SIGNAL : human [1, 20] MA -> donkey [1, 541] MS' - term: id: GO:0006355 label: regulation of DNA-templated transcription evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in supporting_entities: - InterPro:IPR001909 - InterPro:IPR036051 review: summary: Regulation of DNA-templated transcription (InterPro KRAB domain mapping). action: REMOVE reason: This annotation comes from the InterPro KRAB domain of the N-terminal zinc-finger segment, which matches human ZNF786 and is a gene-model merger, not part of PDIA4. PDIA4 is an ER luminal oxidoreductase with no role in transcription regulation. supported_by: - reference_id: file:EQUAS/PDIA4/PDIA4-uniprot.txt record_section: ["DR:InterPro"] supporting_text: InterPro; IPR001909; KRAB. - reference_id: file:EQUAS/PDIA4/PDIA4-bioinformatics/ALT_ENTRY.md supporting_text: 'First 30 residues of A0A8C4PKQ4: MAEPARLPLTFEDVAIYFSEQEWQKLEAWQ' - reference_id: file:EQUAS/PDIA4/PDIA4-bioinformatics/RESULTS-rereview.md supporting_text: 'N-terminal segment vs human ZNF786 (Q8N393, 782 aa): 64.2% identity over 565 paired residues; donkey 1-580, human 1-649' source_defects: - defect_type: OTHER resource: OTHER slot: DB_Object_ID requested_change: CHECK asserted_value: UniProtKB:A0A8C4LTV9 cause: SEQUENCE_MISMAPPING confidence: PROBABLE explanation: 'Resource: Ensembl gene build (propagated into UniProt TrEMBL). The Ensembl donkey gene model ENSEASG00005009014 (PDIA4, transcript ENSEAST00005014006) joins a KRAB-C2H2 zinc-finger segment most similar to human ZNF786 (residues 1-580) to the PDIA4 coding sequence and omits the PDIA4 signal peptide. In human, ZNF786 is a separate gene immediately upstream of PDIA4, and the donkey annotation lacks a ZNF786 gene. Electronic annotations derived from the zinc-finger segment (nucleus, regulation of DNA-templated transcription) are therefore attached to PDIA4 in error; the gene model should be split.' supported_by: - reference_id: file:EQUAS/PDIA4/PDIA4-bioinformatics/RESULTS-rereview.md supporting_text: ENSEASG00005035571 ZNF425 1004371-1014880 strand 1 - term: id: GO:0006457 label: protein folding evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: involved_in supporting_entities: - PANTHER:PTN008566466 review: summary: Protein folding (TreeGrafter). action: ACCEPT reason: PDIA4 catalyses disulfide formation and rearrangement during oxidative folding of secretory proteins in the ER and acts within the BiP/GRP94 chaperone network that binds unfolded substrates; its complex with cyclophilin B accelerates immunoglobulin folding. PAINT placed protein folding at the PDI family root node (PTN000432607), which the TreeGrafter row inherits. supported_by: - reference_id: PMID:16677074 supporting_text: Protein folding in the endoplasmic reticulum is often associated with the formation of native disulfide bonds, a process which in vivo is one of the rate limiting steps of protein folding and which is facilitated by the enzyme protein disulfide isomerase (PDI). - reference_id: PMID:22665516 supporting_text: We have examined in detail a novel ERp72-cyclophilin B complex that enhances the rate of folding of immunoglobulin G. - reference_id: PMID:12475965 supporting_text: This complex is associated with unassembled, incompletely folded immunoglobulin heavy chains. - reference_id: file:EQUAS/PDIA4/PDIA4-bioinformatics/human-P13667-uniprot.txt record_section: ["CC:SUBUNIT"] supporting_text: Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 - term: id: GO:0009986 label: cell surface evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: located_in supporting_entities: - PANTHER:PTN008566466 review: summary: Cell surface (TreeGrafter). action: KEEP_AS_NON_CORE reason: Human ERp72 is released by platelets and relocates to the platelet surface on activation. PAINT placed cell surface at node PTN001448731, whose only experimental donors are human and mouse PDIA4, so the TreeGrafter transfer to the donkey PDIA4 subfamily member is phylogenetically sound. It is a minor, non-core location of an ER-resident protein. supported_by: - reference_id: PMID:19995400 supporting_text: ERp72, ERp57, ERp44 and ERp29 are released by platelets and relocate to the cell surface following platelet activation. - term: id: GO:0034976 label: response to endoplasmic reticulum stress evidence_type: IEA original_reference_id: GO_REF:0000118 qualifier: involved_in supporting_entities: - PANTHER:PTN008566466 review: summary: Response to endoplasmic reticulum stress (TreeGrafter). action: KEEP_AS_NON_CORE reason: ERp72 is one of the classical ER stress proteins, and PAINT placed this term at the PDI family root node PTN000432607 (the separate NOT rows in the family tree sit on other clades, since human PDIA4 retains the IBA). PDIA4 contributes to the response as a folding catalyst for accumulating client proteins rather than as a signalling component, so it is kept as non-core. supported_by: - reference_id: PMID:7916014 supporting_text: Several endoplasmic reticulum stress proteins, including ERp72, interact with thyroglobulin during its maturation. - reference_id: PMID:7916014 supporting_text: These results suggest that ERp72, as well as BiP and grp94, function as molecular chaperones in the maturation of Tg - term: id: GO:0042470 label: melanosome evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0161 review: summary: Melanosome (UniProt subcellular location mapping). action: MARK_AS_OVER_ANNOTATED reason: Based on mass-spectrometric detection of human PDIA4 in melanosome proteomes (about 1500 proteins). ER luminal proteins are common in such organelle preparations and there is no evidence of a melanosome-specific function. supported_by: - reference_id: file:EQUAS/PDIA4/PDIA4-bioinformatics/human-P13667-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: Note=Identified by mass spectrometry in melanosome fractions from stage I to stage IV - reference_id: PMID:17081065 supporting_text: identified approximately 1500 proteins in melanosomes of all stages - term: id: GO:0045454 label: cell redox homeostasis evidence_type: IEA original_reference_id: GO_REF:0000104 qualifier: involved_in supporting_entities: - UniRule:UR000415528 review: summary: Cell redox homeostasis (InterPro thioredoxin-domain mapping). action: MARK_AS_OVER_ANNOTATED reason: The thioredoxin-fold CGHC sites of PDIA4 act on substrate-protein disulfides during oxidative folding in the ER. This is not regulation of cellular redox state. The generic InterPro2GO mapping over-states a role in redox homeostasis. supported_by: - reference_id: PMID:16677074 supporting_text: Protein folding in the endoplasmic reticulum is often associated with the formation of native disulfide bonds, a process which in vivo is one of the rate limiting steps of protein folding and which is facilitated by the enzyme protein disulfide isomerase (PDI). - term: id: GO:0140096 label: catalytic activity, acting on a protein evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: enables supporting_entities: - ARBA:ARBA00027983 review: summary: Catalytic activity, acting on a protein (InterPro mapping). action: TOO_GENERAL reason: True but uninformative; entailed by the accepted protein disulfide isomerase activity. supported_by: - reference_id: file:EQUAS/PDIA4/PDIA4-bioinformatics/RESULTS.md supporting_text: 'DISULFID Redox-active: human [91, 94] CC -> donkey [643, 646] CC' references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms 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:0000104 title: Electronic Gene Ontology annotations created by transferring manual GO annotations between related proteins based on shared sequence features findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000118 title: TreeGrafter-generated GO annotations findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:16677074 title: pH dependence of the peptide thiol-disulfide oxidase activity of six members of the human protein disulfide isomerase family. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Human recombinant ERp72 among six PDI family members assayed for peptide thiol-disulfide oxidase activity; abstract only. - id: file:EQUAS/PDIA4/PDIA4-uniprot.txt title: UniProt record for donkey PDIA4 (A0A8C4LTV9) findings: [] - id: file:EQUAS/PDIA4/PDIA4-bioinformatics/human-P13667-uniprot.txt title: UniProt record for human PDIA4 (P13667) findings: [] - id: file:EQUAS/PDIA4/PDIA4-bioinformatics/RESULTS.md title: 'PDIA4: donkey-human sequence comparison' findings: [] - id: file:EQUAS/PDIA4/PDIA4-bioinformatics/ALT_ENTRY.md title: 'PDIA4: the two donkey PDIA4 UniProt entries' findings: [] - id: PMID:19995400 title: Platelets release novel thiol isomerase enzymes which are recruited to the cell surface following activation. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Abstract states ERp72 is released by human/mouse platelets and relocates to the cell surface after activation; supports the non-core cell surface location. - id: PMID:7916014 title: Several endoplasmic reticulum stress proteins, including ERp72, interact with thyroglobulin during its maturation. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Rat thyroid cell lines (FRTL-5, PCC13); ERp72 crosslinks to maturing thyroglobulin with BiP and GRP94. Supports ER stress protein status and chaperone/folding role. - id: PMID:12475965 title: A subset of chaperones and folding enzymes form multiprotein complexes in endoplasmic reticulum to bind nascent proteins. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: ERp72 is a component of the BiP/GRP94 ER multichaperone complex bound to unfolded Ig heavy chains. - id: PMID:22665516 title: An interaction map of endoplasmic reticulum chaperones and foldases. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: ERp72-cyclophilin B complex enhances IgG folding rate; interaction via polyacidic stretches of ERp72. - id: PMID:17081065 title: Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Large-scale melanosome proteomics; basis for the human melanosome location of PDIA4; no functional data. - id: file:EQUAS/PDIA4/PDIA4-bioinformatics/RESULTS-rereview.md title: 'PDIA4 re-review: locus context and N-terminal segment identity' findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Ensembl REST locus context and segment alignments generated by locus_context_rereview.py during the 2026-10-21 re-review. core_functions: - description: ER luminal protein disulfide isomerase that catalyses formation, reduction and rearrangement of disulfide bonds in client proteins during oxidative folding of secretory proteins, acting within the BiP/GRP94 ER chaperone network. molecular_function: id: GO:0003756 label: protein disulfide isomerase activity directly_involved_in: - id: GO:0006457 label: protein folding locations: - id: GO:0005788 label: endoplasmic reticulum lumen supported_by: - reference_id: PMID:16677074 supporting_text: we have recombinantly expressed and purified six members of the family, PDI, PDIp, ERp57, ERp72, P5, and PDIr from a single organism, human. An examination of the pH-dependence and nature of the rate limiting step for the peptide thiol-disulfide oxidase activity of these enzymes reveals that, with the exception of PDIr, they are all remarkably similar. - reference_id: PMID:16677074 supporting_text: Protein folding in the endoplasmic reticulum is often associated with the formation of native disulfide bonds, a process which in vivo is one of the rate limiting steps of protein folding and which is facilitated by the enzyme protein disulfide isomerase (PDI). - reference_id: PMID:22665516 supporting_text: ERp72-cyclophilin B complex that enhances the rate of folding of immunoglobulin - reference_id: file:EQUAS/PDIA4/PDIA4-bioinformatics/RESULTS.md supporting_text: 'DISULFID Redox-active: human [91, 94] CC -> donkey [643, 646] CC' - reference_id: file:EQUAS/PDIA4/PDIA4-bioinformatics/human-P13667-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen {ECO:0000269|PubMed:12643545}.' suggested_questions: - question: Does the donkey PDIA4 locus encode a conventional ER-targeted ERp72 with a signal peptide (as expected), so that the KRAB-zinc-finger N-terminus of the Ensembl models A0A8C4LTV9/A0A8C4PKQ4 is an annotation fusion with a neighbouring zinc-finger gene? - question: Should the Ensembl donkey gene model ENSEASG00005009014 be split into separate ZNF786 and PDIA4 genes, and are the equivalent horse models (e.g. the 1248-aa PDIA4 entry) affected by the same merger? suggested_experiments: - description: RT-PCR or long-read cDNA sequencing across the 5' end of donkey PDIA4 transcripts to establish whether any transcript joins zinc-finger exons to PDIA4 and to recover the signal-peptide exon.