P4HB encodes protein disulfide-isomerase (PDI, also PDIA1), the prototypical and highly abundant thioredoxin-fold redox enzyme of the endoplasmic reticulum. It has an a-b-b'-a' domain architecture with two catalytically active thioredoxin-like (CGHC) active sites and a C-terminal KDEL ER-retention signal. As an enzyme it catalyzes the formation, breakage and rearrangement (isomerization) of disulfide bonds in nascent and misfolded proteins and can act as a thiol oxidase (with ERO1) or, at the cell surface, as a disulfide reductase. In a redox- and concentration-dependent manner it also functions as a molecular chaperone that suppresses aggregation of misfolded proteins (and at low concentration shows anti-chaperone activity). Beyond its catalytic roles, PDI is the non-catalytic beta-subunit of two ER enzyme complexes; it forms the alpha2beta2 prolyl 4-hydroxylase tetramer (with P4HA1/P4HA2) that hydroxylates proline in collagen, and it is the structural subunit of the microsomal triglyceride transfer protein (MTTP) complex, stabilizing and retaining both enzymes in the ER. It additionally regulates the unfolded-protein-response sensor IRE1/ERN1 (when phosphorylated by FAM20C) and has moonlighting roles at the cell surface and cytoskeleton (LGALS9 receptor, integrin and beta-actin binding, T-cell migration, viral entry). It localizes principally to the ER and ER lumen, with additional pools at the cell membrane, melanosome and cytoskeleton.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006457 protein folding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) annotation of protein folding. PDI catalyzes disulfide-bond formation/isomerization and acts as a redox-dependent chaperone, both of which drive oxidative protein folding. The molecular functions (PDI activity, chaperone) are the more informative annotations. Reason: Protein folding is the broad process outcome of PDI's catalytic and chaperone activities; the disulfide-isomerase MF is the core. Retained as a non-core process. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt This multifunctional protein catalyzes the formation, breakage and rearrangement of disulfide bonds. |
| GO:0009897 external side of plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PDI acts at the external side of the plasma membrane as a cell-surface reductase that cleaves disulfide bonds of cell-attached proteins. A real but secondary site of action. Reason: Cell-surface activity is documented (LGALS9-retained surface reductase) but is a moonlighting pool relative to the principal ER localization. Retained as non-core. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt At the cell surface, seems to act as a reductase that cleaves disulfide bonds of proteins attached to the cell. |
| GO:0003756 protein disulfide isomerase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of protein disulfide isomerase activity (EC 5.3.4.1), the defining core catalytic function of PDI. Reason: Agrees with strong EXP/IDA/TAS evidence for PDI activity; the thioredoxin-fold/CGHC active sites reliably predict this activity. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Catalyzes the rearrangement of -S-S- bonds in proteins. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of ER localization, the principal compartment of PDI (KDEL-retained ER-lumen protein). Reason: Correct principal localization; agrees with abundant IDA/EXP evidence. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of ER lumen localization, the precise compartment where PDI catalyzes oxidative protein folding. Reason: Correct principal localization; agrees with EXP evidence (PMID:23475612). Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic annotation of plasma-membrane localization, consistent with the documented cell-surface pool of PDI (peripheral membrane protein). Reason: A real but secondary cell-surface pool (shedding/replacement from intracellular sources); the ER is the principal compartment. Retained as non-core. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt associated with the plasma membrane |
| GO:0034975 protein folding in endoplasmic reticulum | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Electronic annotation of protein folding in the ER, the principal cellular process to which PDI's disulfide-isomerase and chaperone activities contribute. Reason: A core process context for PDI, but the disulfide-isomerase/chaperone molecular functions are the most informative core annotations; retained as a non-core process. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Inside the cell, seems to form/rearrange disulfide bonds of nascent proteins. |
| GO:0042470 melanosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic annotation of melanosome localization, supported by mass-spectrometry detection of PDI in melanosome fractions. Reason: A documented but secondary/organelle-proteomic localization; peripheral to PDI's core ER function. Retained as non-core. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Identified by mass spectrometry in melanosome fractions from stage I to stage IV |
| GO:0005515 protein binding | IPI PMID:17055437 Redox regulation facilitates optimal peptide selection by MH... | REMOVE | Summary: IntAct interaction (Q03518/TAP1). Bare protein binding is uninformative; an interactome hit. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:19942855 Protein disulphide isomerase is required for signal peptide ... | REMOVE | Summary: IntAct interaction (Q8TCT9/HM13). Bare protein binding is uninformative; an interactome hit. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:20802462 Disulphide production by Ero1Ξ±-PDI relay is rapid and effect... | REMOVE | Summary: IntAct interaction with ERO1A (Q96HE7), the sulfhydryl oxidase that re-oxidizes PDI. Bare protein binding is uninformative; this is a functionally meaningful redox-relay partner. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Interacts with ERO1B |
| GO:0005515 protein binding | IPI PMID:21057456 Recycling of peroxiredoxin IV provides a novel pathway for d... | REMOVE | Summary: IntAct interaction (Q13162/PRDX4). Bare protein binding is uninformative; an interactome hit. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:24098548 Protein disulfide isomerase interacts with tau protein and i... | REMOVE | Summary: IntAct interaction with MAPT/tau (P10636-8). Bare protein binding is uninformative; an interactome hit. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:26370502 Prosaposin facilitates sortilin-independent lysosomal traffi... | REMOVE | Summary: IntAct interaction (P28799/GRN). Bare protein binding is uninformative; an interactome hit. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma... | REMOVE | Summary: IntAct interaction (O15460). Bare protein binding is uninformative; an interactome hit. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:31992623 Binding of Host Cell Surface Protein Disulfide Isomerase by ... | REMOVE | Summary: IntAct interaction (Q2GL86, a viral/microbial protein). Bare protein binding is uninformative; an interactome hit. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: A large membrane-protein interactome screen reporting many PDI partners (PDI is a highly abundant, promiscuous ER protein). Bare protein binding from a broad screen is uninformative. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:32812023 Phosphorylated tau interactome in the human Alzheimer's dise... | REMOVE | Summary: IntAct interaction with MAPT/tau (P10636-8). Bare protein binding is uninformative; an interactome hit. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: A neurodegeneration interactome screen reporting many PDI partners. Bare protein binding from a broad screen of an abundant ER protein is uninformative. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: BioPlex affinity-purification interactome capturing a PDI-O15460 interaction. Bare protein binding is uninformative. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:35063084 Tau interactome maps synaptic and mitochondrial processes as... | REMOVE | Summary: IntAct interaction with MAPT/tau (P10636-8). Bare protein binding is uninformative; an interactome hit. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: Multimodal cell-maps interactome capturing a PDI-O15460 interaction. Bare protein binding is uninformative. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005178 integrin binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation (from mouse P09103) of integrin binding, consistent with the documented cell-surface PDI-integrin interaction. Reason: A documented cell-surface moonlighting interaction (integrin), but secondary to PDI's core ER catalytic function. Retained as non-core. Supporting Evidence: PMID:21670307 Cell surface PDI regulates integrin function on platelets |
| GO:0009897 external side of plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation (from mouse) of external-side plasma-membrane localization, consistent with the cell-surface PDI pool. Reason: A documented but secondary cell-surface localization; the ER is the principal compartment. Retained as non-core. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt associated with the plasma membrane |
| GO:0015035 protein-disulfide reductase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of protein-disulfide reductase activity, one of PDI's documented redox activities (notably at the cell surface). Reason: PDI reductase activity is experimentally demonstrated (EXP PMID:21308844; IDA PMID:16677074, 21670307); the IEA agrees with this core redox function. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt At the cell surface, seems to act as a reductase that cleaves disulfide bonds of proteins attached to the cell. |
| GO:0019899 enzyme binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Generic electronic annotation of enzyme binding (PDI binds ERO1, P4HA, MTTP, ERN1). A non-specific term. Reason: A generic binding term; the specific functional interactions (P4HA, MTTP, ERO1, ERN1) are captured elsewhere. Retained as non-core. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Interacts with ERO1B (PubMed:11707400). |
| GO:0030070 insulin processing | IEA GO_REF:0000107 | UNDECIDED | Summary: Electronic annotation of insulin processing, consistent with PDI's role in oxidative folding of (pro)insulin and other secretory proteins. Reason: A specialized process consequence of PDI's disulfide-isomerase activity. Previously KEEP_AS_NON_CORE; set to UNDECIDED because the only cited support was the GOA row for this annotation, which records the annotation rather than evidence for it. |
| GO:0034663 endoplasmic reticulum chaperone complex | IEA GO_REF:0000107 | UNDECIDED | Summary: Electronic annotation of membership in an ER chaperone complex, consistent with PDI's participation in ER oxidative-folding machinery. Reason: A plausible complex-membership annotation; PDI's specific complexes (P4H, MTTP, ERO1) are captured elsewhere. Previously KEEP_AS_NON_CORE; set to UNDECIDED because the only cited support was the GOA row for this annotation, which records the annotation rather than evidence for it. |
| GO:0044877 protein-containing complex binding | IEA GO_REF:0000107 | UNDECIDED | Summary: Generic electronic annotation of protein-containing complex binding. A non-specific term. Reason: A generic binding term; specific complex interactions are captured elsewhere. Previously KEEP_AS_NON_CORE; set to UNDECIDED because the only cited support was the GOA row for this annotation, which records the annotation rather than evidence for it. |
| GO:0030070 insulin processing | TAS Reactome:R-HSA-264876 | UNDECIDED | Summary: Reactome pathway annotation of insulin processing, consistent with PDI's role in oxidative folding of secretory proteins. Reason: A specialized process consequence of PDI's disulfide-isomerase activity. Previously KEEP_AS_NON_CORE; set to UNDECIDED because the only cited support was the GOA row for this annotation, which records the annotation rather than evidence for it. |
| GO:0035722 interleukin-12-mediated signaling pathway | TAS Reactome:R-HSA-9020591 | UNDECIDED | Summary: Reactome annotation linking PDI to IL-12 signaling, likely reflecting its role in oxidative folding/redox of immune receptors. A specialized pathway context. Reason: A pathway-context annotation peripheral to PDI's core ER catalytic function. Previously KEEP_AS_NON_CORE; set to UNDECIDED because the only cited support was the GOA row for this annotation, which records the annotation rather than evidence for it. |
| GO:0038155 interleukin-23-mediated signaling pathway | TAS Reactome:R-HSA-9020933 | UNDECIDED | Summary: Reactome annotation linking PDI to IL-23 signaling. A specialized pathway context. Reason: A pathway-context annotation peripheral to PDI's core ER catalytic function. Previously KEEP_AS_NON_CORE; set to UNDECIDED because the only cited support was the GOA row for this annotation, which records the annotation rather than evidence for it. |
| GO:0003756 protein disulfide isomerase activity | EXP PMID:15720785 The metallopeptide antibiotic bacitracin inhibits interleuki... | ACCEPT | Summary: Experimental demonstration of PDI's protein disulfide isomerase activity. The defining core catalytic function. Reason: EXP evidence directly supports PDI activity (EC 5.3.4.1), the central function of P4HB. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Catalyzes the rearrangement of -S-S- bonds in proteins. |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) evidence for ER localization, the principal compartment of PDI. Reason: IDA-supported ER localization agrees with the documented principal site. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum |
| GO:0005788 endoplasmic reticulum lumen | EXP PMID:23475612 Loss of both phospholipid and triglyceride transfer activiti... | ACCEPT | Summary: Experimental evidence for ER lumen localization of PDI. Reason: Directly experimentally supported principal localization (KDEL-retained ER-lumen protein). Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Endoplasmic reticulum lumen |
| GO:0015035 protein-disulfide reductase activity | IDA PMID:21670307 Galectin-9 binding to cell surface protein disulfide isomera... | ACCEPT | Summary: Direct evidence that PDI acts as a disulfide reductase at the cell surface, increasing plasma-membrane reductase activity (LGALS9-dependent). A core redox activity. Reason: Directly demonstrated reductase activity; a core PDI redox function (notably at the cell surface). Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt increasing disulfide reductase activity at the plasma membrane |
| GO:2000406 positive regulation of T cell migration | IDA PMID:21670307 Galectin-9 binding to cell surface protein disulfide isomera... | KEEP AS NON CORE | Summary: PDI retained at the Th2 cell surface by LGALS9 increases plasma-membrane reductase activity and enhances T-cell migration. A documented moonlighting process. Reason: A documented (IDA) cell-surface process, but a moonlighting role peripheral to PDI's core ER catalytic function. Retained as non-core. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt altering the plasma membrane redox state and enhancing cell migration |
| GO:0003756 protein disulfide isomerase activity | IDA PMID:32149426 Phosphorylation switches protein disulfide isomerase activit... | ACCEPT | Summary: Direct evidence for PDI disulfide-isomerase activity (with catalytic activity reported); this study also shows FAM20C phosphorylation switches PDI between chaperone and ERN1-regulatory roles. Core catalytic function. Reason: IDA evidence directly supports PDI activity (EC 5.3.4.1); central to P4HB function. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt EC=5.3.4.1 |
| GO:0005783 endoplasmic reticulum | IDA PMID:32149426 Phosphorylation switches protein disulfide isomerase activit... | ACCEPT | Summary: PDI is active in the ER, where it catalyzes oxidative protein folding and regulates ERN1/IRE1A. The principal site of action. Reason: The ER is the principal site where PDI acts; directly supported. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-264997 | ACCEPT | Summary: Reactome annotation placing PDI in the ER lumen, consistent with its principal localization. Reason: Curated ER-lumen localization consistent with the principal site. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-3341296 | KEEP AS NON CORE | Summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. Reason: Redundant curated ER-lumen annotation; consistent but duplicative. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-9817575 | KEEP AS NON CORE | Summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. Reason: Redundant curated ER-lumen annotation; consistent but duplicative. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-1650808 | KEEP AS NON CORE | Summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. Reason: Redundant curated ER-lumen annotation; consistent but duplicative. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-174786 | KEEP AS NON CORE | Summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. Reason: Redundant curated ER-lumen annotation; consistent but duplicative. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-2002460 | KEEP AS NON CORE | Summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. Reason: Redundant curated ER-lumen annotation; consistent but duplicative. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-5358336 | KEEP AS NON CORE | Summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. Reason: Redundant curated ER-lumen annotation; consistent but duplicative. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-5358340 | KEEP AS NON CORE | Summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. Reason: Redundant curated ER-lumen annotation; consistent but duplicative. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8866329 | KEEP AS NON CORE | Summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. Reason: Redundant curated ER-lumen annotation; consistent but duplicative. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8948234 | KEEP AS NON CORE | Summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. Reason: Redundant curated ER-lumen annotation; consistent but duplicative. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8950113 | KEEP AS NON CORE | Summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. Reason: Redundant curated ER-lumen annotation; consistent but duplicative. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8950183 | KEEP AS NON CORE | Summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. Reason: Redundant curated ER-lumen annotation; consistent but duplicative. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8950456 | KEEP AS NON CORE | Summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. Reason: Redundant curated ER-lumen annotation; consistent but duplicative. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8952289 | KEEP AS NON CORE | Summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. Reason: Redundant curated ER-lumen annotation; consistent but duplicative. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-9737780 | KEEP AS NON CORE | Summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. Reason: Redundant curated ER-lumen annotation; consistent but duplicative. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-9918779 | KEEP AS NON CORE | Summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. Reason: Redundant curated ER-lumen annotation; consistent but duplicative. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Endoplasmic reticulum lumen |
| GO:0015035 protein-disulfide reductase activity | EXP PMID:21308844 Protein disulfide isomerase isomerizes non-native disulfide ... | ACCEPT | Summary: Experimental demonstration of PDI protein-disulfide reductase activity. A core redox function. Reason: EXP evidence directly supports reductase activity; a core PDI redox function. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt seems to act as a reductase that cleaves disulfide bonds of proteins attached to the cell. |
| GO:0034975 protein folding in endoplasmic reticulum | IDA PMID:21091435 The endoplasmic reticulum sulfhydryl oxidase Ero1Ξ² drives ef... | KEEP AS NON CORE | Summary: Direct evidence (with ERO1B) that PDI drives efficient oxidative protein folding in the ER. A core process context for PDI. Reason: A core process context, but the disulfide-isomerase/thiol-oxidase molecular functions are the most informative core annotations; retained as a non-core process. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Inside the cell, seems to form/rearrange disulfide bonds of nascent proteins. |
| GO:0003756 protein disulfide isomerase activity | IDA PMID:21091435 The endoplasmic reticulum sulfhydryl oxidase Ero1Ξ² drives ef... | ACCEPT | Summary: Direct evidence for PDI disulfide-isomerase activity coupled to ERO1B-driven oxidative folding. The core catalytic function. Reason: IDA evidence directly supports PDI activity; central to P4HB function. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Catalyzes the rearrangement of -S-S- bonds in proteins. |
| GO:0016972 thiol oxidase activity | IDA PMID:21091435 The endoplasmic reticulum sulfhydryl oxidase Ero1Ξ² drives ef... | ACCEPT | Summary: Direct evidence that PDI can act as a thiol oxidase, accepting oxidizing equivalents from ERO1B to introduce disulfide bonds into substrate proteins. A core redox function. Reason: Directly demonstrated thiol oxidase activity within the ERO1-PDI oxidative-folding relay; a core PDI redox function. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt This multifunctional protein catalyzes the formation, breakage and rearrangement of disulfide bonds. |
| GO:0005515 protein binding | IPI PMID:16478722 Phospholipid transfer activity of microsomal triacylglycerol... | REMOVE | Summary: Interaction with MTTP (P55157), of which PDI is the structural beta-subunit. Bare protein binding is uninformative; the MTTP heterodimerization is a defining structural role. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt heterodimerizes with the protein microsomal triglyceride transfer MTTP |
| GO:0045785 positive regulation of cell adhesion | IMP PMID:24415753 Protein disulfide isomerase directly interacts with Ξ²-actin ... | KEEP AS NON CORE | Summary: PDI (via interaction with beta-actin Cys374) positively regulates cell adhesion. A documented moonlighting process of the cytoplasmic/cytoskeletal PDI pool. Reason: A documented (IMP) cytoskeletal moonlighting process peripheral to PDI's core ER catalytic function. Retained as non-core. Supporting Evidence: PMID:24415753 down-regulation of PDI expression with antisense oligonucleotide abolishes adhesion of the MEG-01 cells to fibronectin and appreciably delays their spreading |
| GO:1900026 positive regulation of substrate adhesion-dependent cell spreading | IMP PMID:24415753 Protein disulfide isomerase directly interacts with Ξ²-actin ... | KEEP AS NON CORE | Summary: PDI positively regulates substrate-adhesion-dependent cell spreading via its beta-actin interaction. A documented moonlighting process. Reason: A documented (IMP) cytoskeletal moonlighting process peripheral to the core ER function. Retained as non-core. Supporting Evidence: PMID:24415753 down-regulation of PDI expression with antisense oligonucleotide abolishes adhesion of the MEG-01 cells to fibronectin and appreciably delays their spreading |
| GO:0003779 actin binding | IPI PMID:24415753 Protein disulfide isomerase directly interacts with Ξ²-actin ... | KEEP AS NON CORE | Summary: PDI directly interacts with beta-actin (ACTB, P60709) at Cys374. A specific molecular function underlying the cytoskeletal moonlighting role. Reason: A directly supported but moonlighting interaction (beta-actin) of the cytoplasmic PDI pool; peripheral to the core ER catalytic function. Retained as non-core. Supporting Evidence: PMID:24415753 Specific interaction of both proteins was demonstrated by a solid phase binding assay, surface plasmon resonance analysis, and immunoprecipitation experiments. |
| GO:0005783 endoplasmic reticulum | IDA PMID:24415753 Protein disulfide isomerase directly interacts with Ξ²-actin ... | ACCEPT | Summary: Direct evidence for ER localization of PDI (in a study also documenting a cytoskeletal pool). The principal compartment. Reason: IDA-supported ER localization agrees with the documented principal site. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum |
| GO:0005829 cytosol | IDA PMID:24415753 Protein disulfide isomerase directly interacts with Ξ²-actin ... | KEEP AS NON CORE | Summary: Direct evidence for a cytosolic/cytoskeletal pool of PDI interacting with beta-actin. A secondary moonlighting localization. Reason: A documented but secondary cytosolic pool; the ER is the principal compartment. Retained as non-core. Supporting Evidence: PMID:24415753 Our data suggest that PDI is released from subcellular compartments to the cytosol and translocated toward the periphery of the cell |
| GO:0005856 cytoskeleton | IDA PMID:24415753 Protein disulfide isomerase directly interacts with Ξ²-actin ... | KEEP AS NON CORE | Summary: Direct evidence for cytoskeletal localization of PDI (beta-actin interaction). A secondary moonlighting localization. Reason: A documented but secondary cytoskeletal pool; peripheral to the core ER function. Retained as non-core. Supporting Evidence: PMID:24415753 PDI colocalizes with Ξ²-actin in adhering MEG-01 cells and predominantly in areas close to the membrane in the lamellipodial protrusions |
| GO:0030027 lamellipodium | IDA PMID:24415753 Protein disulfide isomerase directly interacts with Ξ²-actin ... | KEEP AS NON CORE | Summary: Direct evidence for PDI localization to the lamellipodium, consistent with its beta-actin interaction and cell-spreading role. A secondary moonlighting localization. Reason: A documented but secondary localization of the cytoskeletal pool; peripheral to the core ER function. Retained as non-core. Supporting Evidence: PMID:24415753 PDI colocalizes with Ξ²-actin in adhering MEG-01 cells and predominantly in areas close to the membrane in the lamellipodial protrusions |
| GO:0032991 protein-containing complex | IDA PMID:24415753 Protein disulfide isomerase directly interacts with Ξ²-actin ... | KEEP AS NON CORE | Summary: PDI is part of a protein-containing complex (here a beta-actin-associated complex). A generic complex-membership annotation. Reason: A generic complex term; PDI's defining complexes (P4H, MTTP) are captured elsewhere. Retained as non-core. Supporting Evidence: PMID:24415753 PDI forms a disulfide-bonded complex with Ξ²-actin with a molecular mass of 110 kDa. |
| GO:0015035 protein-disulfide reductase activity | IDA PMID:16677074 pH dependence of the peptide thiol-disulfide oxidase activit... | ACCEPT | Summary: Direct evidence for PDI protein-disulfide reductase activity. A core redox function. Reason: IDA evidence supports reductase activity; a core PDI redox function. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt seems to act as a reductase that cleaves disulfide bonds of proteins attached to the cell. |
| GO:0005515 protein binding | IPI PMID:25108285 Novel missense MTTP gene mutations causing abetalipoproteine... | REMOVE | Summary: Interaction with MTTP (P55157). Bare protein binding is uninformative; the MTTP interaction reflects PDI's structural-subunit role. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:23475612 Loss of both phospholipid and triglyceride transfer activiti... | REMOVE | Summary: Interaction with MTTP (P55157), of which PDI is the structural subunit. Bare protein binding is uninformative. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:26224785 Novel Abetalipoproteinemia Missense Mutation Highlights the ... | REMOVE | Summary: Interaction with MTTP (P55157). Bare protein binding is uninformative; reflects PDI's structural-subunit role. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005783 endoplasmic reticulum | IDA PMID:23475612 Loss of both phospholipid and triglyceride transfer activiti... | ACCEPT | Summary: Direct evidence for ER localization of PDI (colocalizing with MTTP). The principal compartment. Reason: IDA-supported ER localization agrees with the documented principal site. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Colocalizes with MTTP in the endoplasmic reticulum |
| GO:0046982 protein heterodimerization activity | IDA PMID:23475612 Loss of both phospholipid and triglyceride transfer activiti... | ACCEPT | Summary: PDI heterodimerizes with MTTP, forming the microsomal triglyceride transfer protein complex in which PDI is the structural subunit. A core structural molecular function. Reason: Directly demonstrated heterodimerization with MTTP; underlies PDI's role as the structural subunit of the MTTP complex (a genuine non-catalytic core function). Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt heterodimerizes with the protein microsomal triglyceride transfer MTTP |
| GO:0005178 integrin binding | IPI PMID:21670307 Galectin-9 binding to cell surface protein disulfide isomera... | KEEP AS NON CORE | Summary: Interaction with integrin (P05106/ITGB3). Bare integrin binding reflects PDI's cell-surface moonlighting role. Reason: A documented cell-surface moonlighting interaction (integrin); peripheral to PDI's core ER catalytic function. Retained as non-core. The cached abstract shows PDI acting on integrin function; the IPI with ITGB3 defers to the curator's reading of the full text. Supporting Evidence: PMID:21670307 Cell surface PDI regulates integrin function on platelets |
| GO:0046598 positive regulation of viral entry into host cell | IMP PMID:21670307 Galectin-9 binding to cell surface protein disulfide isomera... | KEEP AS NON CORE | Summary: Cell-surface PDI reductase activity reduces disulfide bonds of HIV-1 gp120, facilitating viral entry. A documented moonlighting process. Reason: A documented (IMP) cell-surface moonlighting process; peripheral to the core ER function. Retained as non-core. Supporting Evidence: PMID:21670307 galectin-9 binding to PDI on T cells potentiates infection with HIV |
| GO:0005515 protein binding | IPI PMID:21670307 Galectin-9 binding to cell surface protein disulfide isomera... | REMOVE | Summary: Cell-surface interactions (O00182/LGALS9 and others) underlying PDI's surface reductase/migration role. Bare protein binding is uninformative. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0009897 external side of plasma membrane | IDA PMID:21670307 Galectin-9 binding to cell surface protein disulfide isomera... | KEEP AS NON CORE | Summary: Direct evidence that PDI is retained at the external side of the plasma membrane (LGALS9-dependent). A secondary cell-surface localization. Reason: A documented cell-surface localization, but secondary to the principal ER compartment. Retained as non-core. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt the interaction retains P4HB at the cell surface of Th2 T helper cells |
| GO:0005515 protein binding | IPI PMID:23861867 Nonstructural 5A protein of hepatitis C virus interacts with... | REMOVE | Summary: IntAct interaction (Q03463 processed chain, a viral protein). Bare protein binding is uninformative; an interactome hit. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005925 focal adhesion | HDA PMID:21423176 Analysis of the myosin-II-responsive focal adhesion proteome... | KEEP AS NON CORE | Summary: High-throughput detection of PDI at focal adhesions, consistent with its cell-surface/cytoskeletal moonlighting roles. Reason: A high-throughput proteomic localization; secondary to the principal ER compartment. Retained as non-core. The HDA annotation defers to the curator's reading of the full dataset. Supporting Evidence: PMID:21423176 we performed proteomic analysis of isolated focal adhesions |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | KEEP AS NON CORE | Summary: High-throughput RNA-interactome capture detected PDI as an RNA-bound protein. PDI has no characterized sequence-specific RNA-binding function. Reason: A high-throughput RNA-interactome hit without a defined RNA-binding mechanism; retained as non-core. The HDA annotation defers to the curator's reading of the full dataset. Supporting Evidence: PMID:22658674 Employing two complementary protocols for covalent UV crosslinking of RBPs to RNA |
| GO:0003723 RNA binding | HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ... | KEEP AS NON CORE | Summary: Second RNA-interactome capture dataset detecting PDI, redundant with the first. Reason: A high-throughput RNA-interactome hit without a defined RNA-binding mechanism; retained as non-core. The HDA annotation defers to the curator's reading of the full dataset. Supporting Evidence: PMID:22681889 We developed a photoreactive nucleotide-enhanced UV crosslinking and oligo(dT) purification approach to identify the mRNA-bound proteome using quantitative proteomics |
| GO:0005783 endoplasmic reticulum | IDA PMID:12095988 Role of ubiquilin associated with protein-disulfide isomeras... | ACCEPT | Summary: Direct evidence for ER localization of PDI (UBQLN1-interaction study). The principal compartment. Reason: IDA-supported ER localization agrees with the documented principal site. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum |
| GO:1902175 regulation of oxidative stress-induced intrinsic apoptotic signaling pathway | IMP PMID:12095988 Role of ubiquilin associated with protein-disulfide isomeras... | KEEP AS NON CORE | Summary: PDI (binding UBQLN1) regulates oxidative-stress-induced intrinsic apoptotic signaling. A documented stress-response process. Reason: A documented (IMP) stress-response process; peripheral to PDI's core ER catalytic function. Retained as non-core. Supporting Evidence: PMID:12095988 the overexpression of this gene into neurons protects against apoptotic cell death induced by hypoxia/brain ischemia |
| GO:0004656 procollagen-proline 4-dioxygenase activity | IDA PMID:7753822 Cloning, baculovirus expression, and characterization of a s... | ACCEPT | Summary: PDI is the non-catalytic beta-subunit of prolyl 4-hydroxylase (alpha2beta2 tetramer with P4HA), contributing to procollagen-proline 4-dioxygenase activity by stabilizing the complex and retaining it in the ER. The contributes_to qualifier correctly reflects its structural (not catalytic) role. Reason: PDI is a defining structural subunit of prolyl 4-hydroxylase; contributes_to is the appropriate qualifier for its non-catalytic contribution to the complex's activity. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt this tetramer catalyzes the formation of 4-hydroxyproline in collagen |
| GO:0005515 protein binding | IPI PMID:12095988 Role of ubiquilin associated with protein-disulfide isomeras... | REMOVE | Summary: Interaction with UBQLN1 (Q9UMX0). Bare protein binding is uninformative; an interactome hit linked to ER-stress apoptosis regulation. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Binds UBQLN1 |
| GO:0016222 procollagen-proline 4-dioxygenase complex | IDA PMID:7753822 Cloning, baculovirus expression, and characterization of a s... | ACCEPT | Summary: PDI is the beta-subunit of the procollagen-proline 4-dioxygenase (prolyl 4-hydroxylase) complex. A core structural complex-membership annotation. Reason: Directly supported; PDI is a defining structural component of the prolyl 4-hydroxylase complex. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Interacts with P4HA2, forming a heterotetramer consisting of 2 alpha subunits (P4HA2) and 2 beta (P4HB) |
| GO:0034976 response to endoplasmic reticulum stress | IMP PMID:12095988 Role of ubiquilin associated with protein-disulfide isomeras... | KEEP AS NON CORE | Summary: PDI is involved in the response to ER stress (UPR), consistent with its roles in oxidative folding and ERN1/IRE1A regulation. A documented process. Reason: A genuine ER-stress-response role, but a process consequence of PDI's core catalytic/chaperone functions. Retained as non-core. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt results in attenuation of ERN1 activity |
| GO:0071456 cellular response to hypoxia | IMP PMID:12095988 Role of ubiquilin associated with protein-disulfide isomeras... | KEEP AS NON CORE | Summary: PDI is involved in the cellular response to hypoxia. A documented stress-response process. Reason: A documented (IMP) stress-response process; peripheral to PDI's core ER catalytic function. Retained as non-core. Supporting Evidence: PMID:12095988 protein-disulfide isomerase (PDI) is specifically up-regulated in response to hypoxia/brain ischemia in astrocytes |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | KEEP AS NON CORE | Summary: High-throughput detection of PDI in extracellular exosomes. As a highly abundant ER protein, PDI is frequently detected in exosome preparations. Reason: A high-throughput proteomic detection in exosomes; peripheral to the core ER function. Retained as non-core. The HDA annotation defers to the curator's reading of the full dataset. Supporting Evidence: PMID:19199708 we catalogued 491 proteins in the exosome fraction of human parotid saliva |
| GO:0005783 endoplasmic reticulum | IDA PMID:23152784 Transcriptional regulation of the Ufm1 conjugation system in... | ACCEPT | Summary: Direct evidence for ER localization of PDI. The principal compartment. Reason: IDA-supported ER localization agrees with the documented principal site. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum |
| GO:0003756 protein disulfide isomerase activity | IDA PMID:15225124 Protein disulphide-isomerase reduces ricin to its A and B ch... | ACCEPT | Summary: Direct evidence for PDI disulfide-isomerase activity. The core catalytic function. Reason: IDA evidence directly supports PDI activity; central to P4HB function. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Catalyzes the rearrangement of -S-S- bonds in proteins. PMID:15225124 is impeded by PDI-catalysed formation of heterodimers between endogenous B and A chains derived from reduced holotoxin |
| GO:0005793 endoplasmic reticulum-Golgi intermediate compartment | IDA PMID:15308636 Proteomics of endoplasmic reticulum-Golgi intermediate compa... | KEEP AS NON CORE | Summary: Direct evidence for PDI localization to the ER-Golgi intermediate compartment (ERGIC), consistent with secretory-pathway trafficking. Reason: A documented but secondary localization; the ER lumen is the principal compartment. Retained as non-core. The cached abstract describes the ERGIC membrane proteomics; the IDA defers to the curator's reading of the full text. Supporting Evidence: PMID:15308636 Membranes enriched 110-fold over the homogenate for ERGIC-53 were obtained and analyzed by mass spectrometry. |
| GO:0018401 peptidyl-proline hydroxylation to 4-hydroxy-L-proline | IDA PMID:7753822 Cloning, baculovirus expression, and characterization of a s... | KEEP AS NON CORE | Summary: As the beta-subunit of prolyl 4-hydroxylase, PDI acts upstream of/within peptidyl-proline hydroxylation (collagen 4-hydroxyproline formation). A process consequence of its structural role. Reason: A process annotation arising from PDI's structural subunit role in prolyl 4-hydroxylase; the complex membership / contributes_to MF are the more direct core annotations. Retained as non-core. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt this tetramer catalyzes the formation of 4-hydroxyproline in collagen |
| GO:0005576 extracellular region | NAS PMID:14718574 The human plasma proteome: a nonredundant list developed by ... | KEEP AS NON CORE | Summary: Author-stated extracellular localization of PDI, consistent with its documented secreted/cell-surface pool. Reason: A documented but secondary extracellular pool; the ER is the principal compartment. Retained as non-core. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt seems to be also secreted |
| GO:0003756 protein disulfide isomerase activity | TAS PMID:2846539 Characterization of the human gene for a polypeptide that ac... | ACCEPT | Summary: Author-stated PDI disulfide-isomerase activity, from the classic identification of PDI as both the beta-subunit of prolyl 4-hydroxylase and protein disulfide isomerase. The defining core catalytic function. Reason: PDI activity is the central, well-established function of P4HB; TAS supported. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt Catalyzes the rearrangement of -S-S- bonds in proteins. PMID:2846539 A single polypeptide acts as the beta subunit of prolyl 4-hydroxylase and the enzyme protein disulfide isomerase |
| GO:0004656 procollagen-proline 4-dioxygenase activity | TAS PMID:2846539 Characterization of the human gene for a polypeptide that ac... | MARK AS OVER ANNOTATED | Summary: Author-stated procollagen-proline 4-dioxygenase activity, from the discovery that PDI is the beta-subunit of prolyl 4-hydroxylase. PDI is the structural (non-catalytic) subunit, so the IDA contributes_to annotation is more precise. Reason: PDI is the structural beta-subunit of prolyl 4-hydroxylase and does not itself catalyze proline hydroxylation; the enables/TAS annotation overstates its role. The IDA contributes_to annotation (PMID:7753822) is the appropriate one. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt where P4HB plays the role of a structural subunit |
| GO:0005783 endoplasmic reticulum | TAS PMID:3034602 Molecular cloning of the beta-subunit of human prolyl 4-hydr... | ACCEPT | Summary: Author-stated ER localization of PDI. The principal compartment. Reason: ER localization is the principal, well-established site of PDI. Supporting Evidence: file:human/P4HB/P4HB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum |
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Download this section (compressed HTML)Q: How is PDI's balance between isomerase, oxidase and reductase activities controlled in vivo across the ER lumen and the cell surface, and what sets the redox poise of each pool?
Q: To what extent are PDI's structural-subunit roles (prolyl 4-hydroxylase, MTTP) separable from its catalytic activities, and can one be inhibited without the other?
Q: What is the physiological significance of the cytoskeletal/cell-surface moonlighting pools of PDI relative to its dominant ER oxidative-folding function?
Experiment: Use active-site (CGHC to CGHA/SGHC) PDI mutants to dissect the contributions of the a and a' thioredoxin domains to isomerase, oxidase and reductase activities and to chaperone function.
Experiment: Test whether FAM20C phosphorylation switches PDI between aggregation-suppressing chaperone activity and ERN1/IRE1A binding/attenuation, using phosphomimetic and phospho-dead PDI in UPR reporter assays.
Experiment: Reconstitute prolyl 4-hydroxylase (P4HA2 + P4HB) and MTTP complexes with structural-only PDI variants (catalytically dead) to confirm that the structural-subunit role is independent of disulfide-isomerase catalysis.
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