PDIA4 (ERp72) is an endoplasmic reticulum luminal thiol-disulfide oxidoreductase of the protein disulfide isomerase (PDI) family. The horse protein (645 aa) has an N-terminal signal peptide, an acidic N-terminal stretch, three catalytic thioredoxin-like domains each carrying a CGHC redox-active site, two non-catalytic thioredoxin-fold domains, and a C-terminal REEL ER retrieval signal; it is 90% identical to human ERp72 over its full length. PDIA4 catalyses the oxidation, reduction and isomerization of disulfide bonds in nascent secretory and membrane proteins, and acts within a large ER chaperone network with BiP (HSPA5), GRP94 (HSP90B1), PDI, ERdj3, cyclophilin B, GRP170, UGGT1 and SDF2L1 that binds incompletely folded client proteins such as immunoglobulin heavy chains and thyroglobulin. It is an ER stress-inducible protein, and small amounts are released and found at the cell surface, for example on activated platelets.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003756 protein disulfide isomerase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Protein disulfide isomerase activity inherited from the PDI-family node PTN000432607. Reason: Horse PDIA4 sits in PANTHER subfamily PTHR18929:SF210 with human, mouse, rat and bovine PDIA4, inside the PDI clade to which PAINT curators assigned this activity. All three CGHC redox-active sites are conserved at the human positions, and human ERp72 has peptide thiol-disulfide oxidase activity comparable to PDI. This is the core catalytic activity. Supporting Evidence: PMID:16677074 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. file:HORSE/PDIA4/PDIA4-bioinformatics/RESULTS.md human 91-94 CGHC -> horse 91-94 CGHC file:HORSE/PDIA4/PDIA4-bioinformatics/RESULTS.md human 555-558 CGHC -> horse 555-558 CGHC |
| GO:0003756 protein disulfide isomerase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Protein disulfide isomerase activity from InterPro/EC combined automated annotation. Reason: Consistent with the IBA row; the protein carries the PDIA4-specific InterPro family signature (IPR017068) and conserved CGHC active sites. Supporting Evidence: file:HORSE/PDIA4/PDIA4-uniprot.txt InterPro; IPR017068; Protein_diS-isomerase_A4. file:HORSE/PDIA4/PDIA4-bioinformatics/RESULTS.md human 206-209 CGHC -> horse 206-209 CGHC |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | MODIFY | Summary: Endoplasmic reticulum (PAINT, PDI-family node). Reason: Correct but less specific than the evidence supports. PDIA4 is a soluble luminal protein (signal peptide, no transmembrane segment, C-terminal REEL retrieval motif) and human PDIA4 is experimentally located in the ER lumen, a term this gene already carries. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000432607 · PDI-family node SUPPORTS TRANSFER The family-wide node includes membrane-anchored members, so ER is the right node-level term; for the soluble, KDEL-type-retained PDIA4 the luminal refinement applies. Proposed replacements: endoplasmic reticulum lumen Supporting Evidence: file:HORSE/PDIA4/PDIA4-bioinformatics/human-P13667-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen {ECO:0000269|PubMed:12643545}. file:HORSE/PDIA4/PDIA4-bioinformatics/RESULTS.md horse C-terminal 4 residues: REEL |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000117 | MODIFY | Summary: Endoplasmic reticulum (ARBA). Reason: Same claim as the IBA row; correct but general, refined to the luminal compartment already annotated. Proposed replacements: endoplasmic reticulum lumen Supporting Evidence: file:HORSE/PDIA4/PDIA4-bioinformatics/human-P13667-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen {ECO:0000269|PubMed:12643545}. |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000120 | ACCEPT | Summary: Endoplasmic reticulum lumen. Reason: The horse protein has an N-terminal signal peptide and the C-terminal ER retrieval motif REEL (KEEL in human), and the human ortholog in the same PANTHER subfamily is experimentally located in the ER lumen. This is where PDIA4 acts. Supporting Evidence: file:HORSE/PDIA4/PDIA4-bioinformatics/human-P13667-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen {ECO:0000269|PubMed:12643545}. file:HORSE/PDIA4/PDIA4-uniprot.txt SIGNAL 1..24 PMID:12475965 We demonstrate the existence of a large endoplasmic reticulum (ER)-localized multiprotein complex |
| GO:0006457 protein folding | IBA GO_REF:0000033 | ACCEPT | Summary: Protein folding (PAINT, PDI-family node). Reason: PDIA4 directly does part of oxidative protein folding by catalysing disulfide formation and rearrangement in client proteins, and ERp72 is a component of the ER chaperone complex that binds unfolded nascent proteins and associates with thyroglobulin during its maturation. Supporting Evidence: PMID:16677074 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). PMID:12475965 Our data suggest that this subset of ER chaperones forms an ER network that can bind to unfolded protein substrates PMID:7916014 These results suggest that ERp72, as well as BiP and grp94, function as molecular chaperones in the maturation of Tg |
| GO:0009986 cell surface | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cell surface (PAINT node PTN001448731, seeded by human and mouse PDIA4). Reason: Human ERp72 is released by activated platelets and relocates to the platelet surface; the PAINT node is seeded by PDIA4 orthologs themselves. This is a minor extracellular pool of an ER-resident enzyme, not its main site of action. Supporting Evidence: PMID:19995400 ERp72, ERp57, ERp44 and ERp29 are released by platelets and relocate to the cell surface following platelet activation. |
| GO:0034976 response to endoplasmic reticulum stress | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Response to ER stress (PAINT, PDI-family node). Reason: ERp72 is an ER stress-inducible protein and its folding activity contributes to the ER stress response, and PAINT curators placed this term on the PDI-family node with explicit negations elsewhere in the tree. It is a contextual role downstream of the core folding activity rather than a core function. Supporting Evidence: PMID:7916014 Several endoplasmic reticulum stress proteins, including ERp72, interact with thyroglobulin during its maturation. |
| GO:0042470 melanosome | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | Summary: Melanosome (UniProt subcellular location vocabulary). Reason: The melanosome location for human PDIA4 rests on mass-spectrometry detection in melanosome fractions, which commonly contain ER-derived material; PDIA4 carries an ER retrieval signal and there is no functional evidence that it acts in melanosomes. Propagating this location to horse is an over-annotation. Supporting Evidence: file:HORSE/PDIA4/PDIA4-bioinformatics/human-P13667-uniprot.txt Note=Identified by mass spectrometry in |
| GO:0045454 cell redox homeostasis | IEA GO_REF:0000104 | MARK AS OVER ANNOTATED | Summary: Cell redox homeostasis (UniRule). Reason: PDIA4 is a thiol-disulfide oxidoreductase acting on client protein disulfides during folding; there is no evidence that it regulates the cellular or ER redox state as a homeostatic function. The term reflects a generic mapping for thioredoxin-fold proteins. Supporting Evidence: PMID:16677074 peptide thiol-disulfide oxidase activity |
| GO:0140096 catalytic activity, acting on a protein | IEA GO_REF:0000117 | MODIFY | Summary: Catalytic activity, acting on a protein (ARBA). Reason: True but uninformative; protein disulfide isomerase activity (GO:0003756), already annotated to this gene, is a descendant of this term (verified via OLS ancestors of GO:0003756). Proposed replacements: protein disulfide isomerase activity Supporting Evidence: PMID:16677074 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. |
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Download this section (compressed HTML)Q: Which client proteins depend specifically on ERp72 rather than on PDI or ERp57, given that their in vitro thiol-disulfide oxidase chemistry is very similar?
Experiment: Quantitative proteomics of disulfide-bonded secretory clients (e.g. trapping with CXXA active-site mutants) in cells lacking PDIA4 compared with cells lacking P4HB or PDIA3, to define ERp72-specific substrates.
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Download this section (compressed HTML)Horse length: 645 aa; human length: 645 aa.
Global alignment: 90.08% identity over 645 paired residues; paired coverage 100.0% of human and 100.0% of horse.
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