id: P07237 gene_symbol: P4HB product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: 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. existing_annotations: - term: id: GO:0006457 label: protein folding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: 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. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: This multifunctional protein catalyzes the formation, breakage and rearrangement of disulfide bonds. - term: id: GO:0009897 label: external side of plasma membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: 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. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: At the cell surface, seems to act as a reductase that cleaves disulfide bonds of proteins attached to the cell. - term: id: GO:0003756 label: protein disulfide isomerase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: Electronic annotation of protein disulfide isomerase activity (EC 5.3.4.1), the defining core catalytic function of PDI. action: ACCEPT reason: Agrees with strong EXP/IDA/TAS evidence for PDI activity; the thioredoxin-fold/CGHC active sites reliably predict this activity. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: 'RecName: Full=Protein disulfide-isomerase' - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Electronic annotation of ER localization, the principal compartment of PDI (KDEL-retained ER-lumen protein). action: ACCEPT reason: Correct principal localization; agrees with abundant IDA/EXP evidence. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum' - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Electronic annotation of ER lumen localization, the precise compartment where PDI catalyzes oxidative protein folding. action: ACCEPT reason: Correct principal localization; agrees with EXP evidence (PMID:23475612). supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Endoplasmic reticulum lumen - term: id: GO:0005886 label: plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic annotation of plasma-membrane localization, consistent with the documented cell-surface pool of PDI (peripheral membrane protein). action: KEEP_AS_NON_CORE reason: A real but secondary cell-surface pool (shedding/replacement from intracellular sources); the ER is the principal compartment. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: associated with the plasma membrane - term: id: GO:0034975 label: protein folding in endoplasmic reticulum evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: Electronic annotation of protein folding in the ER, the principal cellular process to which PDI's disulfide-isomerase and chaperone activities contribute. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Inside the cell, seems to form/rearrange disulfide bonds of nascent proteins. - term: id: GO:0042470 label: melanosome evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic annotation of melanosome localization, supported by mass-spectrometry detection of PDI in melanosome fractions. action: KEEP_AS_NON_CORE reason: A documented but secondary/organelle-proteomic localization; peripheral to PDI's core ER function. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Identified by mass spectrometry in melanosome fractions from stage I to stage IV - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17055437 qualifier: enables review: summary: IntAct interaction (Q03518/TAP1). Bare protein binding is uninformative; an interactome hit. action: KEEP_AS_NON_CORE reason: A documented interaction recorded as bare protein binding; uninformative and not core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:17055437 UniProtKB:Q03518 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19942855 qualifier: enables review: summary: IntAct interaction (Q8TCT9/HM13). Bare protein binding is uninformative; an interactome hit. action: KEEP_AS_NON_CORE reason: A documented interaction recorded as bare protein binding; uninformative and not core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:19942855 UniProtKB:Q8TCT9 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20802462 qualifier: enables review: 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. action: KEEP_AS_NON_CORE reason: A real, functionally relevant interaction (ERO1A) recorded as bare protein binding; the catalytic relay is captured by the thiol oxidase MF, so this is kept non-core. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Interacts with ERO1B - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21057456 qualifier: enables review: summary: IntAct interaction (Q13162/PRDX4). Bare protein binding is uninformative; an interactome hit. action: KEEP_AS_NON_CORE reason: A documented interaction recorded as bare protein binding; uninformative and not core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:21057456 UniProtKB:Q13162 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24098548 qualifier: enables review: summary: IntAct interaction with MAPT/tau (P10636-8). Bare protein binding is uninformative; an interactome hit. action: KEEP_AS_NON_CORE reason: A documented interaction recorded as bare protein binding; uninformative and not core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:24098548 UniProtKB:P10636-8 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:26370502 qualifier: enables review: summary: IntAct interaction (P28799/GRN). Bare protein binding is uninformative; an interactome hit. action: KEEP_AS_NON_CORE reason: A documented interaction recorded as bare protein binding; uninformative and not core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:26370502 UniProtKB:P28799 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:30021884 qualifier: enables review: summary: IntAct interaction (O15460). Bare protein binding is uninformative; an interactome hit. action: KEEP_AS_NON_CORE reason: A documented interaction recorded as bare protein binding; uninformative and not core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:30021884 UniProtKB:O15460 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31992623 qualifier: enables review: summary: IntAct interaction (Q2GL86, a viral/microbial protein). Bare protein binding is uninformative; an interactome hit. action: KEEP_AS_NON_CORE reason: A documented interaction recorded as bare protein binding; uninformative and not core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:31992623 UniProtKB:Q2GL86 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: 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. action: KEEP_AS_NON_CORE reason: Bare protein binding from one high-throughput screen with many partners not independently validated; uninformative and not reflective of the core function. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:32296183 UniProtKB:P01137 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32812023 qualifier: enables review: summary: IntAct interaction with MAPT/tau (P10636-8). Bare protein binding is uninformative; an interactome hit. action: KEEP_AS_NON_CORE reason: A documented interaction recorded as bare protein binding; uninformative and not core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:32812023 UniProtKB:P10636-8 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 qualifier: enables review: summary: A neurodegeneration interactome screen reporting many PDI partners. Bare protein binding from a broad screen of an abundant ER protein is uninformative. action: KEEP_AS_NON_CORE reason: Bare protein binding from one high-throughput screen with many partners not independently validated; uninformative and not reflective of the core function. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:32814053 UniProtKB:O43521 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: BioPlex affinity-purification interactome capturing a PDI-O15460 interaction. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: A documented interaction recorded as bare protein binding; uninformative and not core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:33961781 UniProtKB:O15460 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35063084 qualifier: enables review: summary: IntAct interaction with MAPT/tau (P10636-8). Bare protein binding is uninformative; an interactome hit. action: KEEP_AS_NON_CORE reason: A documented interaction recorded as bare protein binding; uninformative and not core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:35063084 UniProtKB:P10636-8 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: Multimodal cell-maps interactome capturing a PDI-O15460 interaction. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: A documented interaction recorded as bare protein binding; uninformative and not core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:40205054 UniProtKB:O15460 - term: id: GO:0005178 label: integrin binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Electronic annotation (from mouse P09103) of integrin binding, consistent with the documented cell-surface PDI-integrin interaction. action: KEEP_AS_NON_CORE reason: A documented cell-surface moonlighting interaction (integrin), but secondary to PDI's core ER catalytic function. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005178 integrin binding IPI PMID:21670307 UniProtKB:P05106 - term: id: GO:0009897 label: external side of plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Electronic annotation (from mouse) of external-side plasma-membrane localization, consistent with the cell-surface PDI pool. action: KEEP_AS_NON_CORE reason: A documented but secondary cell-surface localization; the ER is the principal compartment. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: associated with the plasma membrane - term: id: GO:0015035 label: protein-disulfide reductase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: Electronic annotation of protein-disulfide reductase activity, one of PDI's documented redox activities (notably at the cell surface). action: ACCEPT reason: PDI reductase activity is experimentally demonstrated (EXP PMID:21308844; IDA PMID:16677074, 21670307); the IEA agrees with this core redox function. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: At the cell surface, seems to act as a reductase that cleaves disulfide bonds of proteins attached to the cell. - term: id: GO:0019899 label: enzyme binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Generic electronic annotation of enzyme binding (PDI binds ERO1, P4HA, MTTP, ERN1). A non-specific term. action: KEEP_AS_NON_CORE reason: A generic binding term; the specific functional interactions (P4HA, MTTP, ERO1, ERN1) are captured elsewhere. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0019899 enzyme binding IEA GO_REF:0000107 - term: id: GO:0030070 label: insulin processing evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Electronic annotation of insulin processing, consistent with PDI's role in oxidative folding of (pro)insulin and other secretory proteins. action: KEEP_AS_NON_CORE reason: A specialized process consequence of PDI's disulfide-isomerase activity; retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0030070 insulin processing IEA GO_REF:0000107 - term: id: GO:0034663 label: endoplasmic reticulum chaperone complex evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: part_of review: summary: Electronic annotation of membership in an ER chaperone complex, consistent with PDI's participation in ER oxidative-folding machinery. action: KEEP_AS_NON_CORE reason: A plausible complex-membership annotation; PDI's specific complexes (P4H, MTTP, ERO1) are captured elsewhere. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0034663 endoplasmic reticulum chaperone complex IEA GO_REF:0000107 - term: id: GO:0044877 label: protein-containing complex binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Generic electronic annotation of protein-containing complex binding. A non-specific term. action: KEEP_AS_NON_CORE reason: A generic binding term; specific complex interactions are captured elsewhere. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0044877 protein-containing complex binding IEA GO_REF:0000107 - term: id: GO:0030070 label: insulin processing evidence_type: TAS original_reference_id: Reactome:R-HSA-264876 qualifier: involved_in review: summary: Reactome pathway annotation of insulin processing, consistent with PDI's role in oxidative folding of secretory proteins. action: KEEP_AS_NON_CORE reason: A specialized process consequence of PDI's disulfide-isomerase activity; retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0030070 insulin processing TAS Reactome:R-HSA-264876 - term: id: GO:0035722 label: interleukin-12-mediated signaling pathway evidence_type: TAS original_reference_id: Reactome:R-HSA-9020591 qualifier: involved_in review: summary: Reactome annotation linking PDI to IL-12 signaling, likely reflecting its role in oxidative folding/redox of immune receptors. A specialized pathway context. action: KEEP_AS_NON_CORE reason: A pathway-context annotation peripheral to PDI's core ER catalytic function. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0035722 interleukin-12-mediated signaling pathway TAS Reactome:R-HSA-9020591 - term: id: GO:0038155 label: interleukin-23-mediated signaling pathway evidence_type: TAS original_reference_id: Reactome:R-HSA-9020933 qualifier: involved_in review: summary: Reactome annotation linking PDI to IL-23 signaling. A specialized pathway context. action: KEEP_AS_NON_CORE reason: A pathway-context annotation peripheral to PDI's core ER catalytic function. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0038155 interleukin-23-mediated signaling pathway TAS Reactome:R-HSA-9020933 - term: id: GO:0003756 label: protein disulfide isomerase activity evidence_type: EXP original_reference_id: PMID:15720785 qualifier: enables review: summary: Experimental demonstration of PDI's protein disulfide isomerase activity. The defining core catalytic function. action: ACCEPT reason: EXP evidence directly supports PDI activity (EC 5.3.4.1), the central function of P4HB. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: 'RecName: Full=Protein disulfide-isomerase' - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Direct immunofluorescence (HPA) evidence for ER localization, the principal compartment of PDI. action: ACCEPT reason: IDA-supported ER localization agrees with the documented principal site. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum' - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: EXP original_reference_id: PMID:23475612 qualifier: located_in review: summary: Experimental evidence for ER lumen localization of PDI. action: ACCEPT reason: Directly experimentally supported principal localization (KDEL-retained ER-lumen protein). supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Endoplasmic reticulum lumen - term: id: GO:0015035 label: protein-disulfide reductase activity evidence_type: IDA original_reference_id: PMID:21670307 qualifier: enables review: 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. action: ACCEPT reason: Directly demonstrated reductase activity; a core PDI redox function (notably at the cell surface). supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: increasing disulfide reductase activity at the plasma membrane - term: id: GO:2000406 label: positive regulation of T cell migration evidence_type: IDA original_reference_id: PMID:21670307 qualifier: involved_in review: summary: PDI retained at the Th2 cell surface by LGALS9 increases plasma-membrane reductase activity and enhances T-cell migration. A documented moonlighting process. action: KEEP_AS_NON_CORE reason: A documented (IDA) cell-surface process, but a moonlighting role peripheral to PDI's core ER catalytic function. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: altering the plasma membrane redox state and enhancing cell migration - term: id: GO:0003756 label: protein disulfide isomerase activity evidence_type: IDA original_reference_id: PMID:32149426 qualifier: enables review: 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. action: ACCEPT reason: IDA evidence directly supports PDI activity (EC 5.3.4.1); central to P4HB function. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: 'EC=5.3.4.1' - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IDA original_reference_id: PMID:32149426 qualifier: is_active_in review: summary: PDI is active in the ER, where it catalyzes oxidative protein folding and regulates ERN1/IRE1A. The principal site of action. action: ACCEPT reason: The ER is the principal site where PDI acts; directly supported. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum' - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-264997 qualifier: located_in review: summary: Reactome annotation placing PDI in the ER lumen, consistent with its principal localization. action: ACCEPT reason: Curated ER-lumen localization consistent with the principal site. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Endoplasmic reticulum lumen - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-3341296 qualifier: located_in review: summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. action: KEEP_AS_NON_CORE reason: Redundant curated ER-lumen annotation; consistent but duplicative. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Endoplasmic reticulum lumen - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-9817575 qualifier: located_in review: summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. action: KEEP_AS_NON_CORE reason: Redundant curated ER-lumen annotation; consistent but duplicative. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Endoplasmic reticulum lumen - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-1650808 qualifier: located_in review: summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. action: KEEP_AS_NON_CORE reason: Redundant curated ER-lumen annotation; consistent but duplicative. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Endoplasmic reticulum lumen - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-174786 qualifier: located_in review: summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. action: KEEP_AS_NON_CORE reason: Redundant curated ER-lumen annotation; consistent but duplicative. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Endoplasmic reticulum lumen - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-2002460 qualifier: located_in review: summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. action: KEEP_AS_NON_CORE reason: Redundant curated ER-lumen annotation; consistent but duplicative. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Endoplasmic reticulum lumen - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-5358336 qualifier: located_in review: summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. action: KEEP_AS_NON_CORE reason: Redundant curated ER-lumen annotation; consistent but duplicative. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Endoplasmic reticulum lumen - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-5358340 qualifier: located_in review: summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. action: KEEP_AS_NON_CORE reason: Redundant curated ER-lumen annotation; consistent but duplicative. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Endoplasmic reticulum lumen - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-8866329 qualifier: located_in review: summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. action: KEEP_AS_NON_CORE reason: Redundant curated ER-lumen annotation; consistent but duplicative. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Endoplasmic reticulum lumen - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-8948234 qualifier: located_in review: summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. action: KEEP_AS_NON_CORE reason: Redundant curated ER-lumen annotation; consistent but duplicative. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Endoplasmic reticulum lumen - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-8950113 qualifier: located_in review: summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. action: KEEP_AS_NON_CORE reason: Redundant curated ER-lumen annotation; consistent but duplicative. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Endoplasmic reticulum lumen - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-8950183 qualifier: located_in review: summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. action: KEEP_AS_NON_CORE reason: Redundant curated ER-lumen annotation; consistent but duplicative. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Endoplasmic reticulum lumen - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-8950456 qualifier: located_in review: summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. action: KEEP_AS_NON_CORE reason: Redundant curated ER-lumen annotation; consistent but duplicative. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Endoplasmic reticulum lumen - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-8952289 qualifier: located_in review: summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. action: KEEP_AS_NON_CORE reason: Redundant curated ER-lumen annotation; consistent but duplicative. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Endoplasmic reticulum lumen - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-9737780 qualifier: located_in review: summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. action: KEEP_AS_NON_CORE reason: Redundant curated ER-lumen annotation; consistent but duplicative. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Endoplasmic reticulum lumen - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-9918779 qualifier: located_in review: summary: Reactome annotation placing PDI in the ER lumen; redundant with the principal localization. action: KEEP_AS_NON_CORE reason: Redundant curated ER-lumen annotation; consistent but duplicative. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Endoplasmic reticulum lumen - term: id: GO:0015035 label: protein-disulfide reductase activity evidence_type: EXP original_reference_id: PMID:21308844 qualifier: enables review: summary: Experimental demonstration of PDI protein-disulfide reductase activity. A core redox function. action: ACCEPT reason: EXP evidence directly supports reductase activity; a core PDI redox function. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: seems to act as a reductase that cleaves disulfide bonds of proteins attached to the cell. - term: id: GO:0034975 label: protein folding in endoplasmic reticulum evidence_type: IDA original_reference_id: PMID:21091435 qualifier: involved_in review: summary: Direct evidence (with ERO1B) that PDI drives efficient oxidative protein folding in the ER. A core process context for PDI. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Inside the cell, seems to form/rearrange disulfide bonds of nascent proteins. - term: id: GO:0003756 label: protein disulfide isomerase activity evidence_type: IDA original_reference_id: PMID:21091435 qualifier: enables review: summary: Direct evidence for PDI disulfide-isomerase activity coupled to ERO1B-driven oxidative folding. The core catalytic function. action: ACCEPT reason: IDA evidence directly supports PDI activity; central to P4HB function. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: 'RecName: Full=Protein disulfide-isomerase' - term: id: GO:0016972 label: thiol oxidase activity evidence_type: IDA original_reference_id: PMID:21091435 qualifier: enables review: 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. action: ACCEPT reason: Directly demonstrated thiol oxidase activity within the ERO1-PDI oxidative-folding relay; a core PDI redox function. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: This multifunctional protein catalyzes the formation, breakage and rearrangement of disulfide bonds. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16478722 qualifier: enables review: 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. action: KEEP_AS_NON_CORE reason: A functionally critical interaction (MTTP) recorded here as bare protein binding; the structural role is captured by the protein heterodimerization MF, so this entry is kept non-core. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: heterodimerizes with the protein microsomal triglyceride transfer MTTP - term: id: GO:0045785 label: positive regulation of cell adhesion evidence_type: IMP original_reference_id: PMID:24415753 qualifier: involved_in review: summary: PDI (via interaction with beta-actin Cys374) positively regulates cell adhesion. A documented moonlighting process of the cytoplasmic/cytoskeletal PDI pool. action: KEEP_AS_NON_CORE reason: A documented (IMP) cytoskeletal moonlighting process peripheral to PDI's core ER catalytic function. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0045785 positive regulation of cell adhesion IMP PMID:24415753 - term: id: GO:1900026 label: positive regulation of substrate adhesion-dependent cell spreading evidence_type: IMP original_reference_id: PMID:24415753 qualifier: involved_in review: summary: PDI positively regulates substrate-adhesion-dependent cell spreading via its beta-actin interaction. A documented moonlighting process. action: KEEP_AS_NON_CORE reason: A documented (IMP) cytoskeletal moonlighting process peripheral to the core ER function. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:1900026 positive regulation of substrate adhesion-dependent cell spreading IMP PMID:24415753 - term: id: GO:0003779 label: actin binding evidence_type: IPI original_reference_id: PMID:24415753 qualifier: enables review: summary: PDI directly interacts with beta-actin (ACTB, P60709) at Cys374. A specific molecular function underlying the cytoskeletal moonlighting role. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0003779 actin binding IPI PMID:24415753 UniProtKB:P60709 - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IDA original_reference_id: PMID:24415753 qualifier: located_in review: summary: Direct evidence for ER localization of PDI (in a study also documenting a cytoskeletal pool). The principal compartment. action: ACCEPT reason: IDA-supported ER localization agrees with the documented principal site. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum' - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: PMID:24415753 qualifier: located_in review: summary: Direct evidence for a cytosolic/cytoskeletal pool of PDI interacting with beta-actin. A secondary moonlighting localization. action: KEEP_AS_NON_CORE reason: A documented but secondary cytosolic pool; the ER is the principal compartment. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005829 cytosol IDA PMID:24415753 - term: id: GO:0005856 label: cytoskeleton evidence_type: IDA original_reference_id: PMID:24415753 qualifier: located_in review: summary: Direct evidence for cytoskeletal localization of PDI (beta-actin interaction). A secondary moonlighting localization. action: KEEP_AS_NON_CORE reason: A documented but secondary cytoskeletal pool; peripheral to the core ER function. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005856 cytoskeleton IDA PMID:24415753 - term: id: GO:0030027 label: lamellipodium evidence_type: IDA original_reference_id: PMID:24415753 qualifier: located_in review: summary: Direct evidence for PDI localization to the lamellipodium, consistent with its beta-actin interaction and cell-spreading role. A secondary moonlighting localization. action: KEEP_AS_NON_CORE reason: A documented but secondary localization of the cytoskeletal pool; peripheral to the core ER function. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0030027 lamellipodium IDA PMID:24415753 - term: id: GO:0032991 label: protein-containing complex evidence_type: IDA original_reference_id: PMID:24415753 qualifier: part_of review: summary: PDI is part of a protein-containing complex (here a beta-actin-associated complex). A generic complex-membership annotation. action: KEEP_AS_NON_CORE reason: A generic complex term; PDI's defining complexes (P4H, MTTP) are captured elsewhere. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0032991 protein-containing complex IDA PMID:24415753 - term: id: GO:0015035 label: protein-disulfide reductase activity evidence_type: IDA original_reference_id: PMID:16677074 qualifier: enables review: summary: Direct evidence for PDI protein-disulfide reductase activity. A core redox function. action: ACCEPT reason: IDA evidence supports reductase activity; a core PDI redox function. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: seems to act as a reductase that cleaves disulfide bonds of proteins attached to the cell. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25108285 qualifier: enables review: summary: Interaction with MTTP (P55157). Bare protein binding is uninformative; the MTTP interaction reflects PDI's structural-subunit role. action: KEEP_AS_NON_CORE reason: A functionally critical interaction (MTTP) recorded as bare protein binding; the structural role is captured by the protein heterodimerization MF. Kept non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:25108285 UniProtKB:P55157 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23475612 qualifier: enables review: summary: Interaction with MTTP (P55157), of which PDI is the structural subunit. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: A functionally critical interaction (MTTP) recorded as bare protein binding; captured by the protein heterodimerization MF. Kept non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:23475612 UniProtKB:P55157 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:26224785 qualifier: enables review: summary: Interaction with MTTP (P55157). Bare protein binding is uninformative; reflects PDI's structural-subunit role. action: KEEP_AS_NON_CORE reason: A functionally critical interaction (MTTP) recorded as bare protein binding; captured by the protein heterodimerization MF. Kept non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:26224785 UniProtKB:P55157 - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IDA original_reference_id: PMID:23475612 qualifier: located_in review: summary: Direct evidence for ER localization of PDI (colocalizing with MTTP). The principal compartment. action: ACCEPT reason: IDA-supported ER localization agrees with the documented principal site. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Colocalizes with MTTP in the endoplasmic reticulum - term: id: GO:0046982 label: protein heterodimerization activity evidence_type: IDA original_reference_id: PMID:23475612 qualifier: enables review: summary: PDI heterodimerizes with MTTP, forming the microsomal triglyceride transfer protein complex in which PDI is the structural subunit. A core structural molecular function. action: ACCEPT reason: Directly demonstrated heterodimerization with MTTP; underlies PDI's role as the structural subunit of the MTTP complex (a genuine non-catalytic core function). supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: heterodimerizes with the protein microsomal triglyceride transfer MTTP - term: id: GO:0005178 label: integrin binding evidence_type: IPI original_reference_id: PMID:21670307 qualifier: enables review: summary: Interaction with integrin (P05106/ITGB3). Bare integrin binding reflects PDI's cell-surface moonlighting role. action: KEEP_AS_NON_CORE reason: A documented cell-surface moonlighting interaction (integrin); peripheral to PDI's core ER catalytic function. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005178 integrin binding IPI PMID:21670307 UniProtKB:P05106 - term: id: GO:0046598 label: positive regulation of viral entry into host cell evidence_type: IMP original_reference_id: PMID:21670307 qualifier: involved_in review: summary: Cell-surface PDI reductase activity reduces disulfide bonds of HIV-1 gp120, facilitating viral entry. A documented moonlighting process. action: KEEP_AS_NON_CORE reason: A documented (IMP) cell-surface moonlighting process; peripheral to the core ER function. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0046598 positive regulation of viral entry into host cell IMP PMID:21670307 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21670307 qualifier: enables review: summary: Cell-surface interactions (O00182/LGALS9 and others) underlying PDI's surface reductase/migration role. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Documented cell-surface interactions recorded as bare protein binding; peripheral to the core ER function. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:21670307 UniProtKB:O00182 - term: id: GO:0009897 label: external side of plasma membrane evidence_type: IDA original_reference_id: PMID:21670307 qualifier: located_in review: summary: Direct evidence that PDI is retained at the external side of the plasma membrane (LGALS9-dependent). A secondary cell-surface localization. action: KEEP_AS_NON_CORE reason: A documented cell-surface localization, but secondary to the principal ER compartment. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: the interaction retains P4HB at the cell surface of Th2 T helper cells - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23861867 qualifier: enables review: summary: IntAct interaction (Q03463 processed chain, a viral protein). Bare protein binding is uninformative; an interactome hit. action: KEEP_AS_NON_CORE reason: A documented interaction recorded as bare protein binding; uninformative and not core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:23861867 UniProtKB:Q03463-PRO_0000278740 - term: id: GO:0005925 label: focal adhesion evidence_type: HDA original_reference_id: PMID:21423176 qualifier: located_in review: summary: High-throughput detection of PDI at focal adhesions, consistent with its cell-surface/cytoskeletal moonlighting roles. action: KEEP_AS_NON_CORE reason: A high-throughput proteomic localization; secondary to the principal ER compartment. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005925 focal adhesion HDA PMID:21423176 - term: id: GO:0003723 label: RNA binding evidence_type: HDA original_reference_id: PMID:22658674 qualifier: enables review: summary: High-throughput RNA-interactome capture detected PDI as an RNA-bound protein. PDI has no characterized sequence-specific RNA-binding function. action: KEEP_AS_NON_CORE reason: A high-throughput RNA-interactome hit without a defined RNA-binding mechanism; retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0003723 RNA binding HDA PMID:22658674 - term: id: GO:0003723 label: RNA binding evidence_type: HDA original_reference_id: PMID:22681889 qualifier: enables review: summary: Second RNA-interactome capture dataset detecting PDI, redundant with the first. action: KEEP_AS_NON_CORE reason: A high-throughput RNA-interactome hit without a defined RNA-binding mechanism; retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0003723 RNA binding HDA PMID:22681889 - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IDA original_reference_id: PMID:12095988 qualifier: located_in review: summary: Direct evidence for ER localization of PDI (UBQLN1-interaction study). The principal compartment. action: ACCEPT reason: IDA-supported ER localization agrees with the documented principal site. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum' - term: id: GO:1902175 label: regulation of oxidative stress-induced intrinsic apoptotic signaling pathway evidence_type: IMP original_reference_id: PMID:12095988 qualifier: involved_in review: summary: PDI (binding UBQLN1) regulates oxidative-stress-induced intrinsic apoptotic signaling. A documented stress-response process. action: KEEP_AS_NON_CORE reason: A documented (IMP) stress-response process; peripheral to PDI's core ER catalytic function. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:1902175 regulation of oxidative stress-induced intrinsic apoptotic signaling pathway IMP PMID:12095988 - term: id: GO:0004656 label: procollagen-proline 4-dioxygenase activity evidence_type: IDA original_reference_id: PMID:7753822 qualifier: contributes_to review: 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. action: ACCEPT 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. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: this tetramer catalyzes the formation of 4-hydroxyproline in collagen - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:12095988 qualifier: enables review: summary: Interaction with UBQLN1 (Q9UMX0). Bare protein binding is uninformative; an interactome hit linked to ER-stress apoptosis regulation. action: KEEP_AS_NON_CORE reason: A documented interaction (UBQLN1) recorded as bare protein binding; peripheral to the core function. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Binds UBQLN1 - term: id: GO:0016222 label: procollagen-proline 4-dioxygenase complex evidence_type: IDA original_reference_id: PMID:7753822 qualifier: part_of review: summary: PDI is the beta-subunit of the procollagen-proline 4-dioxygenase (prolyl 4-hydroxylase) complex. A core structural complex-membership annotation. action: ACCEPT reason: Directly supported; PDI is a defining structural component of the prolyl 4-hydroxylase complex. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Interacts with P4HA2, forming a heterotetramer consisting of 2 alpha subunits (P4HA2) and 2 beta (P4HB) - term: id: GO:0034976 label: response to endoplasmic reticulum stress evidence_type: IMP original_reference_id: PMID:12095988 qualifier: involved_in review: 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. action: KEEP_AS_NON_CORE reason: A genuine ER-stress-response role, but a process consequence of PDI's core catalytic/chaperone functions. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: results in attenuation of ERN1 activity - term: id: GO:0071456 label: cellular response to hypoxia evidence_type: IMP original_reference_id: PMID:12095988 qualifier: involved_in review: summary: PDI is involved in the cellular response to hypoxia. A documented stress-response process. action: KEEP_AS_NON_CORE reason: A documented (IMP) stress-response process; peripheral to PDI's core ER catalytic function. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0071456 cellular response to hypoxia IMP PMID:12095988 - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19199708 qualifier: located_in review: summary: High-throughput detection of PDI in extracellular exosomes. As a highly abundant ER protein, PDI is frequently detected in exosome preparations. action: KEEP_AS_NON_CORE reason: A high-throughput proteomic detection in exosomes; peripheral to the core ER function. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0070062 extracellular exosome HDA PMID:19199708 - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IDA original_reference_id: PMID:23152784 qualifier: located_in review: summary: Direct evidence for ER localization of PDI. The principal compartment. action: ACCEPT reason: IDA-supported ER localization agrees with the documented principal site. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum' - term: id: GO:0003756 label: protein disulfide isomerase activity evidence_type: IDA original_reference_id: PMID:15225124 qualifier: enables review: summary: Direct evidence for PDI disulfide-isomerase activity. The core catalytic function. action: ACCEPT reason: IDA evidence directly supports PDI activity; central to P4HB function. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: 'RecName: Full=Protein disulfide-isomerase' - term: id: GO:0005793 label: endoplasmic reticulum-Golgi intermediate compartment evidence_type: IDA original_reference_id: PMID:15308636 qualifier: located_in review: summary: Direct evidence for PDI localization to the ER-Golgi intermediate compartment (ERGIC), consistent with secretory-pathway trafficking. action: KEEP_AS_NON_CORE reason: A documented but secondary localization; the ER lumen is the principal compartment. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-goa.tsv supporting_text: GO:0005793 endoplasmic reticulum-Golgi intermediate compartment IDA PMID:15308636 - term: id: GO:0018401 label: peptidyl-proline hydroxylation to 4-hydroxy-L-proline evidence_type: IDA original_reference_id: PMID:7753822 qualifier: acts_upstream_of_or_within review: 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. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: this tetramer catalyzes the formation of 4-hydroxyproline in collagen - term: id: GO:0005576 label: extracellular region evidence_type: NAS original_reference_id: PMID:14718574 qualifier: located_in review: summary: Author-stated extracellular localization of PDI, consistent with its documented secreted/cell-surface pool. action: KEEP_AS_NON_CORE reason: A documented but secondary extracellular pool; the ER is the principal compartment. Retained as non-core. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: seems to be also secreted - term: id: GO:0003756 label: protein disulfide isomerase activity evidence_type: TAS original_reference_id: PMID:2846539 qualifier: enables review: 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. action: ACCEPT reason: PDI activity is the central, well-established function of P4HB; TAS supported. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: 'RecName: Full=Protein disulfide-isomerase' - term: id: GO:0004656 label: procollagen-proline 4-dioxygenase activity evidence_type: TAS original_reference_id: PMID:2846539 qualifier: enables review: 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. action: MARK_AS_OVER_ANNOTATED 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. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: where P4HB plays the role of a structural subunit - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: TAS original_reference_id: PMID:3034602 qualifier: located_in review: summary: Author-stated ER localization of PDI. The principal compartment. action: ACCEPT reason: ER localization is the principal, well-established site of PDI. supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum' references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:12095988 title: 'Role of ubiquilin associated with protein-disulfide isomerase in the endoplasmic reticulum in stress-induced apoptotic cell death.' findings: - statement: PDI binds UBQLN1 and is involved in regulation of oxidative-stress-induced apoptosis, ER-stress response and hypoxia response. reference_section_type: RESULTS - id: PMID:14718574 title: 'The human plasma proteome: a nonredundant list developed by combination of four separate sources.' findings: [] - id: PMID:15225124 title: 'Protein disulphide-isomerase reduces ricin to its A and B chains in the endoplasmic reticulum.' findings: - statement: PDI catalyzes protein disulfide isomerization. reference_section_type: RESULTS - id: PMID:15308636 title: Proteomics of endoplasmic reticulum-Golgi intermediate compartment (ERGIC) membranes from brefeldin A-treated HepG2 cells identifies ERGIC-32, a new cycling protein that interacts with human Erv46. findings: [] - id: PMID:15720785 title: 'The metallopeptide antibiotic bacitracin inhibits interleukin-12 alphabeta and beta2 secretion.' findings: - statement: PDI exhibits protein disulfide isomerase activity. reference_section_type: RESULTS - id: PMID:16478722 title: 'Phospholipid transfer activity of microsomal triacylglycerol transfer protein is sufficient for the assembly and secretion of apolipoprotein B lipoproteins.' findings: - statement: PDI heterodimerizes with the microsomal triglyceride transfer protein MTTP. reference_section_type: RESULTS - id: PMID:16677074 title: 'pH dependence of the peptide thiol-disulfide oxidase activity of six members of the human protein disulfide isomerase family.' findings: - statement: PDI exhibits protein-disulfide reductase activity. reference_section_type: RESULTS - id: PMID:17055437 title: Redox regulation facilitates optimal peptide selection by MHC class I during antigen processing. findings: [] - id: PMID:19199708 title: Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). findings: [] - id: PMID:19942855 title: 'Protein disulphide isomerase is required for signal peptide peptidase-mediated protein degradation.' findings: [] - id: PMID:20802462 title: Disulphide production by Ero1α-PDI relay is rapid and effectively regulated. findings: - statement: PDI interacts with the sulfhydryl oxidase ERO1A in the oxidative-folding relay. reference_section_type: RESULTS - id: PMID:21057456 title: Recycling of peroxiredoxin IV provides a novel pathway for disulphide formation in the endoplasmic reticulum. findings: [] - id: PMID:21091435 title: 'The endoplasmic reticulum sulfhydryl oxidase Ero1β drives efficient oxidative protein folding with loose regulation.' findings: - statement: PDI, coupled to ERO1B (thiol oxidase activity), drives efficient oxidative protein folding in the ER. reference_section_type: RESULTS - id: PMID:21308844 title: 'Protein disulfide isomerase isomerizes non-native disulfide bonds in human proinsulin independent of its peptide-binding activity.' findings: - statement: PDI exhibits protein-disulfide reductase activity. reference_section_type: RESULTS - id: PMID:21423176 title: Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation. findings: [] - id: PMID:21670307 title: 'Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry.' findings: - statement: LGALS9 retains PDI at the Th2 cell surface, increasing disulfide reductase activity, altering plasma-membrane redox state, enhancing T-cell migration; cell-surface PDI also promotes HIV-1 entry and binds integrin. reference_section_type: RESULTS - id: PMID:22658674 title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. findings: [] - id: PMID:22681889 title: The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. findings: [] - id: PMID:23152784 title: Transcriptional regulation of the Ufm1 conjugation system in response to disturbance of the endoplasmic reticulum homeostasis and inhibition of vesicle trafficking. findings: [] - id: PMID:23475612 title: Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia. findings: - statement: PDI heterodimerizes and colocalizes with MTTP in the ER as the structural subunit of the microsomal triglyceride transfer protein complex. reference_section_type: RESULTS - id: PMID:23861867 title: Nonstructural 5A protein of hepatitis C virus interacts with pyruvate carboxylase and modulates viral propagation. findings: [] - id: PMID:24098548 title: Protein disulfide isomerase interacts with tau protein and inhibits its fibrillization. findings: [] - id: PMID:24415753 title: Protein disulfide isomerase directly interacts with β-actin Cys374 and regulates cytoskeleton reorganization. findings: - statement: PDI directly interacts with beta-actin at Cys374 and positively regulates cell adhesion and substrate-adhesion-dependent cell spreading; localizes to cytosol/cytoskeleton/lamellipodium. reference_section_type: RESULTS - id: PMID:25108285 title: Novel missense MTTP gene mutations causing abetalipoproteinemia. findings: [] - id: PMID:26224785 title: Novel Abetalipoproteinemia Missense Mutation Highlights the Importance of the N-Terminal β-Barrel in Microsomal Triglyceride Transfer Protein Function. findings: - statement: PDI interacts with the N-terminal beta-barrel of MTTP. reference_section_type: RESULTS - id: PMID:26370502 title: Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin. findings: [] - id: PMID:2846539 title: 'Characterization of the human gene for a polypeptide that acts both as the beta subunit of prolyl 4-hydroxylase and as protein disulfide isomerase.' findings: - statement: PDI is identical to the beta-subunit of prolyl 4-hydroxylase and has protein disulfide isomerase activity. reference_section_type: RESULTS reference_review: relevance: HIGH correctness: VERIFIED review_notes: GOA-anchored (this PMID supports GO:0003756 protein disulfide isomerase activity and GO:0004656 procollagen-proline 4-dioxygenase activity in P4HB-goa.tsv); seminal gene-identity paper establishing both PDI catalytic activity and the P4H beta-subunit role - two core functions of P4HB. - id: PMID:30021884 title: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. findings: [] - id: PMID:3034602 title: 'Molecular cloning of the beta-subunit of human prolyl 4-hydroxylase. This subunit and protein disulphide isomerase are products of the same gene.' findings: [] - id: PMID:31992623 title: Binding of Host Cell Surface Protein Disulfide Isomerase by Anaplasma phagocytophilum Asp14 Enables Pathogen Infection. findings: [] - id: PMID:32149426 title: 'Phosphorylation switches protein disulfide isomerase activity to maintain proteostasis and attenuate ER stress.' findings: - statement: FAM20C phosphorylation of PDI switches it between chaperone activity and binding/attenuation of ERN1/IRE1A; PDI has disulfide-isomerase catalytic activity (EC 5.3.4.1) and localizes to the ER. reference_section_type: RESULTS reference_review: relevance: HIGH correctness: VERIFIED review_notes: GOA-anchored (this PMID supports GO:0003756 protein disulfide isomerase activity and GO:0005783 ER in P4HB-goa.tsv); supports the redox-dependent chaperone/UPR-regulatory (ERN1/IRE1) core function of PDI. - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - id: PMID:32812023 title: Phosphorylated tau interactome in the human Alzheimer's disease brain. findings: [] - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:35063084 title: Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration. findings: [] - id: PMID:40205054 title: Multimodal cell maps as a foundation for structural and functional genomics. findings: [] - id: PMID:7753822 title: 'Cloning, baculovirus expression, and characterization of a second mouse prolyl 4-hydroxylase alpha-subunit isoform: formation of an alpha 2 beta 2 tetramer with the protein disulfide-isomerase/beta subunit.' findings: - statement: PDI forms an alpha2beta2 prolyl 4-hydroxylase tetramer with P4HA2 as the structural beta-subunit, catalyzing collagen proline 4-hydroxylation. reference_section_type: RESULTS reference_review: relevance: HIGH correctness: VERIFIED review_notes: GOA-anchored (this PMID supports GO:0004656 procollagen-proline 4-dioxygenase activity and GO:0016222 procollagen-proline 4-dioxygenase complex in P4HB-goa.tsv); establishes PDI as the structural beta-subunit of the alpha2beta2 prolyl 4-hydroxylase tetramer - the non-catalytic structural-subunit core function. - id: Reactome:R-HSA-1650808 title: 'Reactome: PDI in ER lumen.' findings: [] - id: Reactome:R-HSA-174786 title: 'Reactome: PDI in ER lumen.' findings: [] - id: Reactome:R-HSA-2002460 title: 'Reactome: PDI in ER lumen.' findings: [] - id: Reactome:R-HSA-264876 title: 'Reactome: Insulin processing.' findings: [] - id: Reactome:R-HSA-264997 title: 'Reactome: PDI in ER lumen.' findings: [] - id: Reactome:R-HSA-3341296 title: 'Reactome: PDI in ER lumen.' findings: [] - id: Reactome:R-HSA-5358336 title: 'Reactome: PDI in ER lumen.' findings: [] - id: Reactome:R-HSA-5358340 title: 'Reactome: PDI in ER lumen.' findings: [] - id: Reactome:R-HSA-8866329 title: 'Reactome: PDI in ER lumen.' findings: [] - id: Reactome:R-HSA-8948234 title: 'Reactome: PDI in ER lumen.' findings: [] - id: Reactome:R-HSA-8950113 title: 'Reactome: PDI in ER lumen.' findings: [] - id: Reactome:R-HSA-8950183 title: 'Reactome: PDI in ER lumen.' findings: [] - id: Reactome:R-HSA-8950456 title: 'Reactome: PDI in ER lumen.' findings: [] - id: Reactome:R-HSA-8952289 title: 'Reactome: PDI in ER lumen.' findings: [] - id: Reactome:R-HSA-9020591 title: 'Reactome: Interleukin-12 signaling.' findings: [] - id: Reactome:R-HSA-9020933 title: 'Reactome: Interleukin-23 signaling.' findings: [] - id: Reactome:R-HSA-9737780 title: 'Reactome: PDI in ER lumen.' findings: [] - id: Reactome:R-HSA-9817575 title: 'Reactome: PDI in ER lumen.' findings: [] - id: Reactome:R-HSA-9918779 title: 'Reactome: PDI in ER lumen.' findings: [] - id: file:human/P4HB/P4HB-uniprot.txt title: UniProt entry P07237 (PDIA1_HUMAN), Protein disulfide-isomerase / P4HB findings: - statement: Multifunctional ER thioredoxin-fold protein that catalyzes formation/breakage/rearrangement of disulfide bonds (PDI activity, EC 5.3.4.1), acts as thiol oxidase/reductase and redox-dependent chaperone, is the structural beta-subunit of prolyl 4-hydroxylase and of the MTTP complex, regulates ERN1/IRE1A, and has cell-surface/cytoskeletal moonlighting roles. reference_section_type: OTHER core_functions: - description: Protein disulfide-isomerase that catalyzes the formation, breakage and rearrangement (isomerization) of disulfide bonds during oxidative protein folding in the ER (EC 5.3.4.1). molecular_function: id: GO:0003756 label: protein disulfide isomerase activity locations: - id: GO:0005788 label: endoplasmic reticulum lumen supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: This multifunctional protein catalyzes the formation, breakage and rearrangement of disulfide bonds. - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: 'RecName: Full=Protein disulfide-isomerase' - description: Thiol-disulfide oxidoreductase activities (thiol oxidase, accepting oxidizing equivalents from ERO1, and protein-disulfide reductase, notably at the cell surface) that introduce or cleave disulfide bonds in substrate proteins. molecular_function: id: GO:0015035 label: protein-disulfide reductase activity locations: - id: GO:0005788 label: endoplasmic reticulum lumen - id: GO:0009897 label: external side of plasma membrane supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: At the cell surface, seems to act as a reductase that cleaves disulfide bonds of proteins attached to the cell. - description: Non-catalytic structural subunit role; PDI is the beta-subunit of the alpha2beta2 prolyl 4-hydroxylase tetramer (with P4HA1/P4HA2) and the structural subunit of the microsomal triglyceride transfer protein (MTTP) complex, stabilizing and retaining both enzymes in the ER. molecular_function: id: GO:0046982 label: protein heterodimerization activity locations: - id: GO:0005788 label: endoplasmic reticulum lumen supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: Interacts with P4HA2, forming a heterotetramer consisting of 2 alpha subunits (P4HA2) and 2 beta (P4HB) - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: heterodimerizes with the protein microsomal triglyceride transfer MTTP - description: Redox-dependent molecular chaperone that (at high concentration, following FAM20C phosphorylation) suppresses aggregation of misfolded proteins and regulates the UPR sensor ERN1/IRE1A. molecular_function: id: GO:0044183 label: protein folding chaperone locations: - id: GO:0005788 label: endoplasmic reticulum lumen supported_by: - reference_id: file:human/P4HB/P4HB-uniprot.txt supporting_text: functions as a chaperone that inhibits aggregation of misfolded proteins proposed_new_terms: [] suggested_questions: - question: 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? - question: 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? - question: What is the physiological significance of the cytoskeletal/cell-surface moonlighting pools of PDI relative to its dominant ER oxidative-folding function? suggested_experiments: - description: 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. - description: 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. - description: 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.