PDIA4 (ERp72) is a soluble protein disulfide isomerase family member of the endoplasmic reticulum lumen. The mature protein has five thioredoxin-like domains arranged a0-a-b-b'-a', of which the a0, a and a' domains carry CGHC redox-active sites, an acidic N-terminal stretch, and a C-terminal KEEL ER-retention signal. It catalyses thiol-disulfide exchange reactions (oxidation, reduction and isomerization of disulfide bonds) on client proteins, assisting the oxidative folding of a relatively narrow set of secretory proteins, binding misfolded disulfide-containing proteins such as mutant matrilin-3, and favouring ER retention of misfolded substrates. It associates with other ER chaperones and foldases, including cyclophilin B, with which it accelerates immunoglobulin folding, but unlike ERp57 it does not bind calnexin. PDIA4 is induced by ER stress. A fraction is released from platelets and relocates to the activated platelet surface, where its a and a' active sites support platelet aggregation and thrombosis. It is also a host factor for human astrovirus genome uncoating.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | MARK AS OVER ANNOTATED | Summary: RNA binding from HeLa mRNA interactome capture (UV crosslinking followed by oligo-dT pulldown and mass spectrometry). Reason: PDIA4 is a signal-peptide-bearing, KEEL-retained resident of the ER lumen, topologically separated from cytosolic mRNA. A single high-throughput interactome-capture hit, with no RNA-binding domain and no follow-up, is more plausibly a post-lysis or abundant-protein artefact than a physiological activity. Not part of PDIA4 function. Supporting Evidence: PMID:22658674 we describe a systematic, unbiased, and comprehensive approach, termed "interactome capture," to define the mRNA interactome of proliferating human HeLa cells file:human/PDIA4/PDIA4-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0003756 protein disulfide isomerase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Protein disulfide isomerase activity propagated by PAINT from the PDI-family node PTN000432607; seeds include mouse Pdia4 (MGI:104864), the one-to-one ortholog in PTHR18929:SF210. Reason: PDIA4 has three CGHC thioredoxin-like active sites in an a0-a-b-b'-a' architecture, is in the PDIA4 subfamily (PTHR18929:SF210) together with the IBD seed mouse Pdia4, and recombinant human ERp72 shows PDI-like thiol-disulfide chemistry. The inheritance of the ancestral isomerase activity by this subfamily is well supported. This is the core activity. Supporting Evidence: PMID:2295602 ERp72 appears to be a newly described member of the family of CGHC-containing proteins PMID:16677074 we have recombinantly expressed and purified six members of the family, PDI, PDIp, ERp57, ERp72, P5, and PDIr from a single organism, human PMID:16677074 with the exception of PDIr, they are all remarkably similar file:human/PDIA4/PDIA4-uniprot.txt Belongs to the protein disulfide isomerase family. |
| GO:0003756 protein disulfide isomerase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Protein disulfide isomerase activity from InterPro signatures (including PDIA4-specific IPR017068) and EC 5.3.4.1 mapping. Reason: Consistent with the subfamily membership and the CGHC active sites; agrees with the IBA and ISS rows. Supporting Evidence: file:human/PDIA4/PDIA4-uniprot.txt Belongs to the protein disulfide isomerase family. PMID:2295602 ERp72 appears to be a newly described member of the family of CGHC-containing proteins |
| GO:0003756 protein disulfide isomerase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Protein disulfide isomerase activity transferred from mouse Pdia4 (P08003), a same-subfamily ortholog. Reason: Mouse Pdia4 is in the same PANTHER subfamily (PTHR18929:SF210); mouse ERp72 activity and its dependence on the CGHC motifs is established in PMID:28576878. Transfer to the human ortholog is appropriate. In human, direct biochemistry (PMID:16677074) supports the thiol-disulfide oxidoreductase chemistry; an isomerization assay on the human protein is not in the cached literature, so this activity in human rests on orthology plus the human oxidase data. Supporting Evidence: PMID:2295602 ERp72 appears to be a newly described member of the family of CGHC-containing proteins PMID:16677074 we have recombinantly expressed and purified six members of the family, PDI, PDIp, ERp57, ERp72, P5, and PDIr from a single organism, human PMID:28576878 ERp72 plays a critical role in platelet function and coagulation through the a and a |
| GO:0003756 protein disulfide isomerase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Protein disulfide isomerase activity transferred from rat Pdia4 (P38659), a same-subfamily ortholog. Reason: Rat ERp72 is a one-to-one ortholog in PTHR18929:SF210; its structure shows three catalytic sites facing a central cleft as expected for a PDI. Consistent with the other rows for this term. Supporting Evidence: PMID:20600112 A structural model of full-length ERp72 shows that all three catalytic sites roughly face each other PMID:2295602 ERp72 appears to be a newly described member of the family of CGHC-containing proteins |
| GO:0005515 protein binding | IPI PMID:16287128 Multiple epiphyseal dysplasia mutations in MATN3 cause misfo... | MODIFY | Summary: Interaction with matrilin-3 (MATN3); ERp72 associates selectively with misfolded multiple epiphyseal dysplasia mutant matrilin-3 A-domains, not wild type. Reason: The cited work shows that ERp72 binds mutant, misfolded matrilin-3 (A-domain) retained in the ER, while wild-type A-domain does not co-precipitate; a substrate-trapping ERp72 mutant forms mixed disulfides with substrates. The informative activity is misfolded protein binding, consistent with PDIA4 acting as a foldase on misfolded disulfide-containing clients. Proposed replacements: misfolded protein binding Supporting Evidence: PMID:16287128 showed that only the mutant A-domains co-precipitated with ERp72 PMID:23956175 SDS–PAGE and western blotting demonstrated that ERp72, Creld2 and Armet were co-precipitated with mutant matrilin-3 alone |
| GO:0005515 protein binding | IPI PMID:22190034 Global landscape of HIV-human protein complexes. | REMOVE | Summary: Interaction with an HIV-1 protein (Q76353) from a global affinity-purification mass spectrometry screen. Reason: Generic protein binding is uninformative and is removed per the repository protein-binding policy; removal does not mean the reported interaction is false. A high-throughput virus-host AP-MS hit with an abundant ER chaperone does not indicate a specific molecular function. |
| GO:0005515 protein binding | IPI PMID:22665516 An interaction map of endoplasmic reticulum chaperones and f... | REMOVE | Summary: Interaction with cyclophilin B (PPIB), mapped in an ER chaperone/foldase interaction study. Reason: Generic protein binding is uninformative and is removed per the repository protein-binding policy; removal does not mean the reported interaction is false. The ERp72-cyclophilin B complex is real and functionally relevant to folding (captured here under protein folding in ER), but no specific binding MF term captures it better than generic protein binding; the polyacidic stretches of ERp72 engage a conserved CypB surface. Supporting Evidence: PMID:22665516 We have examined in detail a novel ERp72-cyclophilin B complex that enhances the rate of folding of immunoglobulin G. |
| GO:0005515 protein binding | IPI PMID:22665516 An interaction map of endoplasmic reticulum chaperones and f... | REMOVE | Summary: Interaction with cyclophilin B (PPIB), mapped in an ER chaperone/foldase interaction study. Reason: Generic protein binding is uninformative and is removed per the repository protein-binding policy; removal does not mean the reported interaction is false. The ERp72-cyclophilin B complex is real and functionally relevant to folding (captured here under protein folding in ER), but no specific binding MF term captures it better than generic protein binding; the polyacidic stretches of ERp72 engage a conserved CypB surface. Supporting Evidence: PMID:22665516 We have examined in detail a novel ERp72-cyclophilin B complex that enhances the rate of folding of immunoglobulin G. |
| GO:0005515 protein binding | IPI PMID:23956175 Armet/Manf and Creld2 are components of a specialized ER str... | MODIFY | Summary: Interaction with matrilin-3 (MATN3); ERp72 associates selectively with misfolded multiple epiphyseal dysplasia mutant matrilin-3 A-domains, not wild type. Reason: The cited work shows that ERp72 binds mutant, misfolded matrilin-3 (A-domain) retained in the ER, while wild-type A-domain does not co-precipitate; a substrate-trapping ERp72 mutant forms mixed disulfides with substrates. The informative activity is misfolded protein binding, consistent with PDIA4 acting as a foldase on misfolded disulfide-containing clients. Proposed replacements: misfolded protein binding Supporting Evidence: PMID:16287128 showed that only the mutant A-domains co-precipitated with ERp72 PMID:23956175 SDS–PAGE and western blotting demonstrated that ERp72, Creld2 and Armet were co-precipitated with mutant matrilin-3 alone |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Interaction with UniProtKB:Q9NPA0 from a proteome-scale interactome screen (AP-MS or yeast two-hybrid). Reason: Generic protein binding is uninformative and is removed per the repository protein-binding policy; removal does not mean the reported interaction is false. High-throughput binary/AP-MS hits (EMC7, keratin-associated proteins, LCN2) give no functional information about PDIA4; keratin-associated protein Y2H hits for a luminal ER protein are likely non-physiological. |
| GO:0005515 protein binding | IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma... | REMOVE | Summary: Interaction with PPIB from crosslinking mass spectrometry in intact nuclei. Reason: Generic protein binding is uninformative and is removed per the repository protein-binding policy; removal does not mean the reported interaction is false. Large-scale crosslinking hit; the CypB association is discussed under the PMID:22665516 rows. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Interaction with UniProtKB:P59990 from a proteome-scale interactome screen (AP-MS or yeast two-hybrid). Reason: Generic protein binding is uninformative and is removed per the repository protein-binding policy; removal does not mean the reported interaction is false. High-throughput binary/AP-MS hits (EMC7, keratin-associated proteins, LCN2) give no functional information about PDIA4; keratin-associated protein Y2H hits for a luminal ER protein are likely non-physiological. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Interaction with UniProtKB:P60410 from a proteome-scale interactome screen (AP-MS or yeast two-hybrid). Reason: Generic protein binding is uninformative and is removed per the repository protein-binding policy; removal does not mean the reported interaction is false. High-throughput binary/AP-MS hits (EMC7, keratin-associated proteins, LCN2) give no functional information about PDIA4; keratin-associated protein Y2H hits for a luminal ER protein are likely non-physiological. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Interaction with UniProtKB:P80188 from a proteome-scale interactome screen (AP-MS or yeast two-hybrid). Reason: Generic protein binding is uninformative and is removed per the repository protein-binding policy; removal does not mean the reported interaction is false. High-throughput binary/AP-MS hits (EMC7, keratin-associated proteins, LCN2) give no functional information about PDIA4; keratin-associated protein Y2H hits for a luminal ER protein are likely non-physiological. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Interaction with UniProtKB:Q9BYQ6 from a proteome-scale interactome screen (AP-MS or yeast two-hybrid). Reason: Generic protein binding is uninformative and is removed per the repository protein-binding policy; removal does not mean the reported interaction is false. High-throughput binary/AP-MS hits (EMC7, keratin-associated proteins, LCN2) give no functional information about PDIA4; keratin-associated protein Y2H hits for a luminal ER protein are likely non-physiological. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Interaction with UniProtKB:Q9NPA0 from a proteome-scale interactome screen (AP-MS or yeast two-hybrid). Reason: Generic protein binding is uninformative and is removed per the repository protein-binding policy; removal does not mean the reported interaction is false. High-throughput binary/AP-MS hits (EMC7, keratin-associated proteins, LCN2) give no functional information about PDIA4; keratin-associated protein Y2H hits for a luminal ER protein are likely non-physiological. |
| GO:0005576 extracellular region | IDA PMID:19995400 Platelets release novel thiol isomerase enzymes which are re... | KEEP AS NON CORE | Summary: Extracellular region: ERp72 is released by resting and activated human platelets. Reason: Experimental and consistent with the documented platelet release and extracellular function in thrombosis; peripheral to the main ER-lumenal role. Supporting Evidence: PMID:19995400 ERp72, ERp57, ERp44 and ERp29 are released by platelets and relocate to the cell surface following platelet activation |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: ER localization propagated from PTN000432607; human PDIA4 is itself one of the experimental seeds. Reason: PDIA4 is a soluble ER resident retained by its C-terminal KEEL signal. The more specific ER lumen term is also annotated. Supporting Evidence: PMID:2295602 both sequences are endoplasmic reticulum retention signals for their respective proteins file:human/PDIA4/PDIA4-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: ER localization by immunofluorescence (Human Protein Atlas). Reason: Consistent with all other evidence for ER residence. Supporting Evidence: PMID:2295602 both sequences are endoplasmic reticulum retention signals for their respective proteins |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000117 | ACCEPT | Summary: ER localization from an ARBA rule. Reason: Correct; independently supported by the KEEL retention experiments and ER lumen localization. Supporting Evidence: PMID:2295602 both sequences are endoplasmic reticulum retention signals for their respective proteins file:human/PDIA4/PDIA4-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | EXP PMID:12643545 Proteomic analysis of early melanosomes: identification of n... | ACCEPT | Summary: ER lumen, as recorded by UniProt from an organellar proteomics study. Reason: ER lumen is the principal location of PDIA4: it has an N-terminal signal peptide and a C-terminal KEEL ER-retention signal whose removal causes secretion. Defer to the curator for this specific citation. Supporting Evidence: file:human/PDIA4/PDIA4-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen PMID:2295602 both sequences are endoplasmic reticulum retention signals for their respective proteins |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000120 | ACCEPT | Summary: ER lumen from InterPro/SubCell mapping. Reason: Correct and core location. Supporting Evidence: PMID:2295602 both sequences are endoplasmic reticulum retention signals for their respective proteins file:human/PDIA4/PDIA4-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | TAS PMID:2295602 ERp72, an abundant luminal endoplasmic reticulum protein, co... | ACCEPT | Summary: ER lumen: ERp72 was described as an abundant luminal ER protein with a KEEL retention signal. Reason: The paper showed that KEEL is a functional ER retention signal for ERp72. Supporting Evidence: PMID:2295602 both sequences are endoplasmic reticulum retention signals for their respective proteins PMID:2295602 ERp72, an abundant luminal endoplasmic reticulum protein |
| GO:0006457 protein folding | IBA GO_REF:0000033 | MODIFY | Summary: Protein folding propagated from PTN000432607 (PDI family root). Reason: PDIA4 participates in folding by catalysing disulfide formation/rearrangement in client proteins in the ER lumen: in human hepatoma cells it overlaps with PDI in albumin oxidative folding, it binds misfolded disulfide-bonded clients, and with cyclophilin B it accelerates IgG folding. The general term is correct but less specific than the evidence supports; protein folding in endoplasmic reticulum (GO:0034975) is the precise process, and is what PDIA4 contributes to. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000432607 SUPPORTS TRANSFER Deep PDI-family node; folding participation is inherited by the PDIA4 subfamily, but the generic parent is propagated instead of folding in the ER lumen. Proposed replacements: protein folding in endoplasmic reticulum Supporting Evidence: PMID:20660153 Our data highlighting the apparent functional overlap of PDI and ERp72 in Alb oxidation PMID:22665516 We have examined in detail a novel ERp72-cyclophilin B complex that enhances the rate of folding of immunoglobulin G. PMID:16287128 showed that only the mutant A-domains co-precipitated with ERp72 |
| GO:0006457 protein folding | ISS GO_REF:0000024 | MODIFY | Summary: Protein folding transferred from rat Pdia4 (P38659). Reason: PDIA4 participates in folding by catalysing disulfide formation/rearrangement in client proteins in the ER lumen: in human hepatoma cells it overlaps with PDI in albumin oxidative folding, it binds misfolded disulfide-bonded clients, and with cyclophilin B it accelerates IgG folding. The general term is correct but less specific than the evidence supports; protein folding in endoplasmic reticulum (GO:0034975) is the precise process, and is what PDIA4 contributes to. Proposed replacements: protein folding in endoplasmic reticulum Supporting Evidence: PMID:20660153 Our data highlighting the apparent functional overlap of PDI and ERp72 in Alb oxidation PMID:22665516 We have examined in detail a novel ERp72-cyclophilin B complex that enhances the rate of folding of immunoglobulin G. |
| GO:0009306 protein secretion | TAS PMID:2295602 ERp72, an abundant luminal endoplasmic reticulum protein, co... | REMOVE | Summary: Protein secretion, attributed to a study of ERp72 cDNA and its KEEL ER-retention signal. Reason: The paper showed that deleting KEEL causes ERp72 itself to be secreted, i.e. ERp72 was the cargo whose secretion was measured, and its retention depends on the KDEL-receptor system. This does not show that ERp72 performs any step of protein secretion. The function of the KEEL motif is retention, not secretion. Supporting Evidence: PMID:2295602 both sequences are endoplasmic reticulum retention signals for their respective proteins |
| GO:0009986 cell surface | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cell surface propagated from PTN001448731 (Eumetazoa), seeded by human PDIA4 and mouse Pdia4 platelet data. Reason: Human ERp72 relocates to the platelet surface after activation, and mouse/human platelet studies indicate a surface-acting role through its CGHC sites (generation of thiols in integrin alphaIIb-beta3). The target appearing in its own seed list reflects its experimental grounding. Real but secondary to the ER-lumenal function. Supporting Evidence: PMID:19995400 ERp72, ERp57, ERp44 and ERp29 are released by platelets and relocate to the cell surface following platelet activation PMID:28576878 Aggregation and ATP secretion of human platelets was potentiated by ERp72(oo-ss-ss) |
| GO:0009986 cell surface | IDA PMID:19995400 Platelets release novel thiol isomerase enzymes which are re... | KEEP AS NON CORE | Summary: Cell surface: ERp72 detected on the surface of activated human platelets by flow cytometry and surface biotinylation. Reason: Experimental; secondary location relevant to haemostasis. Supporting Evidence: PMID:19995400 ERp72, ERp57, ERp44 and ERp29 are released by platelets and relocate to the cell surface following platelet activation |
| GO:0015035 protein-disulfide reductase activity | IDA PMID:16677074 pH dependence of the peptide thiol-disulfide oxidase activit... | ACCEPT | Summary: Thiol-disulfide oxidoreductase activity: recombinant human ERp72 catalysed peptide thiol-disulfide oxidation with pH dependence similar to PDI. Reason: GO:0015035 is defined by the reversible reaction protein dithiol = protein disulfide (its synonyms include protein disulfide oxidoreductase activity), so the measured peptide dithiol oxidation by purified human ERp72 directly supports it. Core biochemical activity of the three CGHC sites. Supporting Evidence: PMID:16677074 we have recombinantly expressed and purified six members of the family, PDI, PDIp, ERp57, ERp72, P5, and PDIr from a single organism, human PMID:16677074 with the exception of PDIr, they are all remarkably similar |
| GO:0015035 protein-disulfide reductase activity | IEA GO_REF:0000117 | ACCEPT | Summary: Protein-disulfide reductase activity from an ARBA rule. Reason: Agrees with direct human biochemistry (PMID:16677074) and the insulin-reduction assays showing all three thioredoxin domains are catalytic. Supporting Evidence: PMID:16677074 we have recombinantly expressed and purified six members of the family, PDI, PDIp, ERp57, ERp72, P5, and PDIr from a single organism, human PMID:16333982 All domains contributed to apparent steady-state binding (Km) and catalysis at saturating substrate concentrations (kcat) |
| GO:0034976 response to endoplasmic reticulum stress | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Response to ER stress propagated from PTN000432607 (seeds: yeast PDI1, human P4HB, Arabidopsis PDIs). Reason: PDIA4 is a classic UPR-inducible ER foldase, strongly up-regulated when misfolded disulfide-bonded proteins accumulate (e.g. mutant matrilin-3 models), and it acts on those misfolded clients. The IBA is reasonable at the family level, but the term mostly reflects stress-inducible expression and folding capacity rather than a distinct signalling role; non-core. Supporting Evidence: PMID:23956175 Interestingly, of the 20 most significantly up-regulated genes, three were members of the PDIA protein family, namely Pdia3/Erp57, Pdia4/Erp72 and Pdia6/P5 PMID:23956175 SDS–PAGE and western blotting demonstrated that ERp72, Creld2 and Armet were co-precipitated with mutant matrilin-3 alone |
| GO:0042470 melanosome | EXP PMID:17081065 Proteomic and bioinformatic characterization of the biogenes... | KEEP AS NON CORE | Summary: Melanosome: identified by mass spectrometry in melanosome fractions from stage I to IV. Reason: Organellar proteomics of melanosomes identifies many ER and other shared proteins; PDIA4 detection likely reflects ER contribution to early melanosome biogenesis or fraction overlap, and there is no evidence for a melanosome-specific function. Kept as a non-core observed location, deferring to curators. Supporting Evidence: PMID:17081065 identified approximately 1500 proteins in melanosomes of all stages file:human/PDIA4/PDIA4-uniprot.txt Identified by mass spectrometry in |
| GO:0042470 melanosome | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Melanosome from SubCell/ARBA mapping, derived from the proteomics observation. Reason: Same basis as the EXP row; non-core. Supporting Evidence: PMID:12643545 56 proteins that are shared with other organelles |
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Download this section (compressed HTML)Q: Which endogenous human client proteins depend specifically on ERp72, given its narrow substrate specificity and lack of calnexin binding?
Q: Should human PDIA4 carry a platelet-function process term? Mouse Pdia4 has acts_upstream_of_or_within IMP annotations to platelet aggregation and blood coagulation (PMID:28576878) that PAINT did not propagate; is the integrin alphaIIb-beta3 thiol modification a direct catalytic step that would justify involved_in?
Q: Is the ER chaperone multiprotein complex membership (GO:0034663; mouse IDA) also established for human PDIA4?
Experiment: Substrate-trapping (CXXA) ERp72 proteomics in human secretory cells (e.g. hepatocytes, plasma cells) to define its specific clients.
Experiment: Direct disulfide isomerization assays (e.g. scrambled RNase A refolding) on purified human ERp72 and single active-site mutants to establish isomerase activity in the human protein.
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