Existing Annotations Review

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 RecName: Full=Protein disulfide-isomerase
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...	KEEP AS NON CORE	Summary: IntAct interaction (Q03518/TAP1). Bare protein binding is uninformative; an interactome hit. Reason: A documented interaction recorded as bare protein binding; uninformative and not core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005515 protein binding IPI PMID:17055437 UniProtKB:Q03518
GO:0005515 protein binding	IPI PMID:19942855 Protein disulphide isomerase is required for signal peptide ...	KEEP AS NON CORE	Summary: IntAct interaction (Q8TCT9/HM13). Bare protein binding is uninformative; an interactome hit. Reason: A documented interaction recorded as bare protein binding; uninformative and not core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005515 protein binding IPI PMID:19942855 UniProtKB:Q8TCT9
GO:0005515 protein binding	IPI PMID:20802462 Disulphide production by Ero1α-PDI relay is rapid and effect...	KEEP AS NON CORE	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: 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. 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...	KEEP AS NON CORE	Summary: IntAct interaction (Q13162/PRDX4). Bare protein binding is uninformative; an interactome hit. Reason: A documented interaction recorded as bare protein binding; uninformative and not core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005515 protein binding IPI PMID:21057456 UniProtKB:Q13162
GO:0005515 protein binding	IPI PMID:24098548 Protein disulfide isomerase interacts with tau protein and i...	KEEP AS NON CORE	Summary: IntAct interaction with MAPT/tau (P10636-8). Bare protein binding is uninformative; an interactome hit. Reason: A documented interaction recorded as bare protein binding; uninformative and not core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005515 protein binding IPI PMID:24098548 UniProtKB:P10636-8
GO:0005515 protein binding	IPI PMID:26370502 Prosaposin facilitates sortilin-independent lysosomal traffi...	KEEP AS NON CORE	Summary: IntAct interaction (P28799/GRN). Bare protein binding is uninformative; an interactome hit. Reason: A documented interaction recorded as bare protein binding; uninformative and not core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005515 protein binding IPI PMID:26370502 UniProtKB:P28799
GO:0005515 protein binding	IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma...	KEEP AS NON CORE	Summary: IntAct interaction (O15460). Bare protein binding is uninformative; an interactome hit. Reason: A documented interaction recorded as bare protein binding; uninformative and not core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005515 protein binding IPI PMID:30021884 UniProtKB:O15460
GO:0005515 protein binding	IPI PMID:31992623 Binding of Host Cell Surface Protein Disulfide Isomerase by ...	KEEP AS NON CORE	Summary: IntAct interaction (Q2GL86, a viral/microbial protein). Bare protein binding is uninformative; an interactome hit. Reason: A documented interaction recorded as bare protein binding; uninformative and not core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005515 protein binding IPI PMID:31992623 UniProtKB:Q2GL86
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	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 protein binding from one high-throughput screen with many partners not independently validated; uninformative and not reflective of the core function. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005515 protein binding IPI PMID:32296183 UniProtKB:P01137
GO:0005515 protein binding	IPI PMID:32812023 Phosphorylated tau interactome in the human Alzheimer's dise...	KEEP AS NON CORE	Summary: IntAct interaction with MAPT/tau (P10636-8). Bare protein binding is uninformative; an interactome hit. Reason: A documented interaction recorded as bare protein binding; uninformative and not core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005515 protein binding IPI PMID:32812023 UniProtKB:P10636-8
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	KEEP AS NON CORE	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 protein binding from one high-throughput screen with many partners not independently validated; uninformative and not reflective of the core function. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005515 protein binding IPI PMID:32814053 UniProtKB:O43521
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: BioPlex affinity-purification interactome capturing a PDI-O15460 interaction. Bare protein binding is uninformative. Reason: A documented interaction recorded as bare protein binding; uninformative and not core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005515 protein binding IPI PMID:33961781 UniProtKB:O15460
GO:0005515 protein binding	IPI PMID:35063084 Tau interactome maps synaptic and mitochondrial processes as...	KEEP AS NON CORE	Summary: IntAct interaction with MAPT/tau (P10636-8). Bare protein binding is uninformative; an interactome hit. Reason: A documented interaction recorded as bare protein binding; uninformative and not core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005515 protein binding IPI PMID:35063084 UniProtKB:P10636-8
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	KEEP AS NON CORE	Summary: Multimodal cell-maps interactome capturing a PDI-O15460 interaction. Bare protein binding is uninformative. Reason: A documented interaction recorded as bare protein binding; uninformative and not core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005515 protein binding IPI PMID:40205054 UniProtKB:O15460
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: file:human/P4HB/P4HB-goa.tsv GO:0005178 integrin binding IPI PMID:21670307 UniProtKB:P05106
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-goa.tsv GO:0019899 enzyme binding IEA GO_REF:0000107
GO:0030070 insulin processing	IEA GO_REF:0000107	KEEP AS NON CORE	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; retained as non-core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0030070 insulin processing IEA GO_REF:0000107
GO:0034663 endoplasmic reticulum chaperone complex	IEA GO_REF:0000107	KEEP AS NON CORE	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. Retained as non-core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0034663 endoplasmic reticulum chaperone complex IEA GO_REF:0000107
GO:0044877 protein-containing complex binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Generic electronic annotation of protein-containing complex binding. A non-specific term. Reason: A generic binding term; specific complex interactions are captured elsewhere. Retained as non-core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0044877 protein-containing complex binding IEA GO_REF:0000107
GO:0030070 insulin processing	TAS Reactome:R-HSA-264876	KEEP AS NON CORE	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; retained as non-core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0030070 insulin processing TAS Reactome:R-HSA-264876
GO:0035722 interleukin-12-mediated signaling pathway	TAS Reactome:R-HSA-9020591	KEEP AS NON CORE	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. Retained as non-core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0035722 interleukin-12-mediated signaling pathway TAS Reactome:R-HSA-9020591
GO:0038155 interleukin-23-mediated signaling pathway	TAS Reactome:R-HSA-9020933	KEEP AS NON CORE	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. Retained as non-core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0038155 interleukin-23-mediated signaling pathway TAS Reactome:R-HSA-9020933
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 RecName: Full=Protein disulfide-isomerase
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 Ero1β 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 Ero1β 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 RecName: Full=Protein disulfide-isomerase
GO:0016972 thiol oxidase activity	IDA PMID:21091435 The endoplasmic reticulum sulfhydryl oxidase Ero1β 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...	KEEP AS NON CORE	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: 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. 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 β-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: file:human/P4HB/P4HB-goa.tsv GO:0045785 positive regulation of cell adhesion IMP PMID:24415753
GO:1900026 positive regulation of substrate adhesion-dependent cell spreading	IMP PMID:24415753 Protein disulfide isomerase directly interacts with β-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: file:human/P4HB/P4HB-goa.tsv GO:1900026 positive regulation of substrate adhesion-dependent cell spreading IMP PMID:24415753
GO:0003779 actin binding	IPI PMID:24415753 Protein disulfide isomerase directly interacts with β-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: file:human/P4HB/P4HB-goa.tsv GO:0003779 actin binding IPI PMID:24415753 UniProtKB:P60709
GO:0005783 endoplasmic reticulum	IDA PMID:24415753 Protein disulfide isomerase directly interacts with β-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 β-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: file:human/P4HB/P4HB-goa.tsv GO:0005829 cytosol IDA PMID:24415753
GO:0005856 cytoskeleton	IDA PMID:24415753 Protein disulfide isomerase directly interacts with β-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: file:human/P4HB/P4HB-goa.tsv GO:0005856 cytoskeleton IDA PMID:24415753
GO:0030027 lamellipodium	IDA PMID:24415753 Protein disulfide isomerase directly interacts with β-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: file:human/P4HB/P4HB-goa.tsv GO:0030027 lamellipodium IDA PMID:24415753
GO:0032991 protein-containing complex	IDA PMID:24415753 Protein disulfide isomerase directly interacts with β-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: file:human/P4HB/P4HB-goa.tsv GO:0032991 protein-containing complex IDA PMID:24415753
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...	KEEP AS NON CORE	Summary: Interaction with MTTP (P55157). Bare protein binding is uninformative; the MTTP interaction reflects PDI's structural-subunit role. Reason: A functionally critical interaction (MTTP) recorded as bare protein binding; the structural role is captured by the protein heterodimerization MF. Kept non-core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005515 protein binding IPI PMID:25108285 UniProtKB:P55157
GO:0005515 protein binding	IPI PMID:23475612 Loss of both phospholipid and triglyceride transfer activiti...	KEEP AS NON CORE	Summary: Interaction with MTTP (P55157), of which PDI is the structural subunit. Bare protein binding is uninformative. Reason: A functionally critical interaction (MTTP) recorded as bare protein binding; captured by the protein heterodimerization MF. Kept non-core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005515 protein binding IPI PMID:23475612 UniProtKB:P55157
GO:0005515 protein binding	IPI PMID:26224785 Novel Abetalipoproteinemia Missense Mutation Highlights the ...	KEEP AS NON CORE	Summary: Interaction with MTTP (P55157). Bare protein binding is uninformative; reflects PDI's structural-subunit role. Reason: A functionally critical interaction (MTTP) recorded as bare protein binding; captured by the protein heterodimerization MF. Kept non-core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005515 protein binding IPI PMID:26224785 UniProtKB:P55157
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. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005178 integrin binding IPI PMID:21670307 UniProtKB:P05106
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: file:human/P4HB/P4HB-goa.tsv GO:0046598 positive regulation of viral entry into host cell IMP PMID:21670307
GO:0005515 protein binding	IPI PMID:21670307 Galectin-9 binding to cell surface protein disulfide isomera...	KEEP AS NON CORE	Summary: Cell-surface interactions (O00182/LGALS9 and others) underlying PDI's surface reductase/migration role. Bare protein binding is uninformative. Reason: Documented cell-surface interactions recorded as bare protein binding; peripheral to the core ER function. Retained as non-core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005515 protein binding IPI PMID:21670307 UniProtKB:O00182
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...	KEEP AS NON CORE	Summary: IntAct interaction (Q03463 processed chain, a viral protein). Bare protein binding is uninformative; an interactome hit. Reason: A documented interaction recorded as bare protein binding; uninformative and not core. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005515 protein binding IPI PMID:23861867 UniProtKB:Q03463-PRO_0000278740
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. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005925 focal adhesion HDA PMID:21423176
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. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0003723 RNA binding HDA PMID:22658674
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. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0003723 RNA binding HDA PMID:22681889
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: file:human/P4HB/P4HB-goa.tsv GO:1902175 regulation of oxidative stress-induced intrinsic apoptotic signaling pathway IMP PMID:12095988
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...	KEEP AS NON CORE	Summary: Interaction with UBQLN1 (Q9UMX0). Bare protein binding is uninformative; an interactome hit linked to ER-stress apoptosis regulation. Reason: A documented interaction (UBQLN1) recorded as bare protein binding; peripheral to the core function. Retained as non-core. 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: file:human/P4HB/P4HB-goa.tsv GO:0071456 cellular response to hypoxia IMP PMID:12095988
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. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0070062 extracellular exosome HDA PMID:19199708
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 RecName: Full=Protein disulfide-isomerase
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. Supporting Evidence: file:human/P4HB/P4HB-goa.tsv GO:0005793 endoplasmic reticulum-Golgi intermediate compartment IDA PMID:15308636
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 RecName: Full=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

Core Functions

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:

protein disulfide isomerase activity

Cellular Locations:

endoplasmic reticulum lumen

Supporting Evidence:

file:human/P4HB/P4HB-uniprot.txt
This multifunctional protein catalyzes the formation, breakage and rearrangement of disulfide bonds.
file:human/P4HB/P4HB-uniprot.txt
RecName: Full=Protein disulfide-isomerase

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:

protein-disulfide reductase activity

Cellular Locations:

endoplasmic reticulum lumen external side of plasma membrane

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.

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:

protein heterodimerization activity

Cellular Locations:

endoplasmic reticulum lumen

Supporting Evidence:

file:human/P4HB/P4HB-uniprot.txt
Interacts with P4HA2, forming a heterotetramer consisting of 2 alpha subunits (P4HA2) and 2 beta (P4HB)
file:human/P4HB/P4HB-uniprot.txt
heterodimerizes with the protein microsomal triglyceride transfer MTTP

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:

protein folding chaperone

Cellular Locations:

endoplasmic reticulum lumen

Supporting Evidence:

file:human/P4HB/P4HB-uniprot.txt
functions as a chaperone that inhibits aggregation of misfolded proteins

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:12095988

Role of ubiquilin associated with protein-disulfide isomerase in the endoplasmic reticulum in stress-induced apoptotic cell death.

PDI binds UBQLN1 and is involved in regulation of oxidative-stress-induced apoptosis, ER-stress response and hypoxia response.

PMID:14718574

The human plasma proteome: a nonredundant list developed by combination of four separate sources.

PMID:15225124

Protein disulphide-isomerase reduces ricin to its A and B chains in the endoplasmic reticulum.

PDI catalyzes protein disulfide isomerization.

PMID:15308636

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.

PMID:15720785

The metallopeptide antibiotic bacitracin inhibits interleukin-12 alphabeta and beta2 secretion.

PDI exhibits protein disulfide isomerase activity.

PMID:16478722

Phospholipid transfer activity of microsomal triacylglycerol transfer protein is sufficient for the assembly and secretion of apolipoprotein B lipoproteins.

PDI heterodimerizes with the microsomal triglyceride transfer protein MTTP.

PMID:16677074

pH dependence of the peptide thiol-disulfide oxidase activity of six members of the human protein disulfide isomerase family.

PDI exhibits protein-disulfide reductase activity.

PMID:17055437

Redox regulation facilitates optimal peptide selection by MHC class I during antigen processing.

PMID:19199708

Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).

PMID:19942855

Protein disulphide isomerase is required for signal peptide peptidase-mediated protein degradation.

PMID:20802462

Disulphide production by Ero1α-PDI relay is rapid and effectively regulated.

PDI interacts with the sulfhydryl oxidase ERO1A in the oxidative-folding relay.

PMID:21057456

Recycling of peroxiredoxin IV provides a novel pathway for disulphide formation in the endoplasmic reticulum.

PMID:21091435

The endoplasmic reticulum sulfhydryl oxidase Ero1β drives efficient oxidative protein folding with loose regulation.

PDI, coupled to ERO1B (thiol oxidase activity), drives efficient oxidative protein folding in the ER.

PMID:21308844

Protein disulfide isomerase isomerizes non-native disulfide bonds in human proinsulin independent of its peptide-binding activity.

PDI exhibits protein-disulfide reductase activity.

PMID:21423176

Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation.

PMID:21670307

Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry.

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.

PMID:22658674

Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.

PMID:22681889

The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.

PMID:23152784

Transcriptional regulation of the Ufm1 conjugation system in response to disturbance of the endoplasmic reticulum homeostasis and inhibition of vesicle trafficking.

PMID:23475612

Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia.

PDI heterodimerizes and colocalizes with MTTP in the ER as the structural subunit of the microsomal triglyceride transfer protein complex.

PMID:23861867

Nonstructural 5A protein of hepatitis C virus interacts with pyruvate carboxylase and modulates viral propagation.

PMID:24098548

Protein disulfide isomerase interacts with tau protein and inhibits its fibrillization.

PMID:24415753

Protein disulfide isomerase directly interacts with β-actin Cys374 and regulates cytoskeleton reorganization.

PDI directly interacts with beta-actin at Cys374 and positively regulates cell adhesion and substrate-adhesion-dependent cell spreading; localizes to cytosol/cytoskeleton/lamellipodium.

PMID:25108285

Novel missense MTTP gene mutations causing abetalipoproteinemia.

PMID:26224785

Novel Abetalipoproteinemia Missense Mutation Highlights the Importance of the N-Terminal β-Barrel in Microsomal Triglyceride Transfer Protein Function.

PDI interacts with the N-terminal beta-barrel of MTTP.

PMID:26370502

Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin.

PMID:2846539

Characterization of the human gene for a polypeptide that acts both as the beta subunit of prolyl 4-hydroxylase and as protein disulfide isomerase.

PDI is identical to the beta-subunit of prolyl 4-hydroxylase and has protein disulfide isomerase activity.

PMID:30021884

Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.

PMID:3034602

Molecular cloning of the beta-subunit of human prolyl 4-hydroxylase. This subunit and protein disulphide isomerase are products of the same gene.

PMID:31992623

Binding of Host Cell Surface Protein Disulfide Isomerase by Anaplasma phagocytophilum Asp14 Enables Pathogen Infection.

PMID:32149426

Phosphorylation switches protein disulfide isomerase activity to maintain proteostasis and attenuate ER stress.

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.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32812023

Phosphorylated tau interactome in the human Alzheimer's disease brain.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35063084

Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

PMID:7753822

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.

PDI forms an alpha2beta2 prolyl 4-hydroxylase tetramer with P4HA2 as the structural beta-subunit, catalyzing collagen proline 4-hydroxylation.

Reactome:R-HSA-1650808

Reactome: PDI in ER lumen.

Reactome:R-HSA-174786

Reactome: PDI in ER lumen.

Reactome:R-HSA-2002460

Reactome: PDI in ER lumen.

Reactome:R-HSA-264876

Reactome: Insulin processing.

Reactome:R-HSA-264997

Reactome: PDI in ER lumen.

Reactome:R-HSA-3341296

Reactome: PDI in ER lumen.

Reactome:R-HSA-5358336

Reactome: PDI in ER lumen.

Reactome:R-HSA-5358340

Reactome: PDI in ER lumen.

Reactome:R-HSA-8866329

Reactome: PDI in ER lumen.

Reactome:R-HSA-8948234

Reactome: PDI in ER lumen.

Reactome:R-HSA-8950113

Reactome: PDI in ER lumen.

Reactome:R-HSA-8950183

Reactome: PDI in ER lumen.

Reactome:R-HSA-8950456

Reactome: PDI in ER lumen.

Reactome:R-HSA-8952289

Reactome: PDI in ER lumen.

Reactome:R-HSA-9020591

Reactome: Interleukin-12 signaling.

Reactome:R-HSA-9020933

Reactome: Interleukin-23 signaling.

Reactome:R-HSA-9737780

Reactome: PDI in ER lumen.

Reactome:R-HSA-9817575

Reactome: PDI in ER lumen.

Reactome:R-HSA-9918779

Reactome: PDI in ER lumen.

file:human/P4HB/P4HB-uniprot.txt

UniProt entry P07237 (PDIA1_HUMAN), Protein disulfide-isomerase / P4HB

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.

Suggested Experiments

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.

📚 Additional Documentation

Notes

(P4HB-notes.md)

P4HB (PDI / PDIA1) research notes

UniProt: P07237. EC 5.3.4.1 (protein disulfide isomerase). Prototypical ER thioredoxin-fold
redox protein. Multidomain: a-b-b'-a' thioredoxin-like domains with two catalytic CXXC (a, a')
active sites; C-terminal KDEL ER-retention.

Core multifunctional biology (well-established)

Catalyzes formation, breakage and REARRANGEMENT of disulfide bonds [uniprot "This multifunctional
protein catalyzes the formation, breakage and rearrangement of disulfide bonds"]. PDI activity
EXP/IDA/TAS (PMID:15720785, 15225124, 21091435, 32149426, 2846539). EC 5.3.4.1.
Also has thiol oxidase activity (GO:0016972 IDA PMID:21091435, with ERO1B) and protein-disulfide
REDUCTASE activity (GO:0015035 EXP/IDA PMID:21308844, 16677074, 21670307). At the cell surface
acts as a reductase cleaving disulfide bonds of cell-attached proteins.
Redox-dependent CHAPERONE: at high concentration + FAM20C phosphorylation inhibits aggregation
of misfolded proteins (chaperone); at low concentration facilitates aggregation (anti-chaperone)
[uniprot]. protein folding in ER (GO:0034975 IDA PMID:21091435), response to ER stress, ER
chaperone complex.
STRUCTURAL beta-subunit of prolyl 4-hydroxylase: forms alpha2beta2 tetramer with P4HA1/2; P4HB
is the structural subunit, contributes_to procollagen-proline 4-dioxygenase activity (GO:0004656
IDA/TAS PMID:7753822, 2846539), part of procollagen-proline 4-dioxygenase complex (GO:0016222),
peptidyl-proline hydroxylation (GO:0018401) [uniprot "Interacts with P4HA2, forming a
heterotetramer... where P4HB plays the role of a structural subunit"].
STRUCTURAL subunit of microsomal triglyceride transfer protein (MTTP/MTP): heterodimerizes with
MTTP (GO:0046982 IDA PMID:23475612; partner P55157=MTTP), stabilizes/retains it in ER without
contributing to catalysis [uniprot]. protein-containing complex.
ERN1/IRE1A regulation: FAM20C-phosphorylated PDI binds ERN1 and attenuates its activity
(UPR regulation) PMID:32149426.
Cell-surface/immune roles: LGALS9 receptor retaining PDI at Th2 cell surface, increasing reductase
activity, enhancing T cell migration (GO:2000406 IDA PMID:21670307); integrin binding (P05106=ITGB3);
positive regulation of viral entry (HIV gp120 reduction; GO:0046598 IMP PMID:21670307); IL-12/IL-23
signaling (Reactome TAS).
beta-actin Cys374 interaction regulating actin (cytoplasmic/cytoskeletal pool): actin binding
GO:0003779 (IPI PMID:24415753 P60709=ACTB), positive regulation of cell adhesion/spreading,
lamellipodium/cytoskeleton localization PMID:24415753.
Insulin processing (GO:0030070 IEA/TAS).

Subcellular location

ER (primary), ER lumen, melanosome, cell membrane (peripheral; cell surface, shedding), ERGIC,
extracellular (NAS/exosome), focal adhesion/cytoskeleton/lamellipodium (actin pool). RNA binding
(HDA, mRNA interactome) — non-core.

Action plan

PDI activity GO:0003756 (EXP/IDA/TAS/IEA): ACCEPT core MF.
protein-disulfide reductase activity GO:0015035 (EXP/IDA/IEA): ACCEPT (core; cell-surface reductase).
thiol oxidase activity GO:0016972 (IDA): ACCEPT (with ERO1).
procollagen-proline 4-dioxygenase activity GO:0004656 (IDA contributes_to/TAS): ACCEPT — structural
beta-subunit; contributes_to is correct (not catalytic itself).
procollagen-proline 4-dioxygenase complex GO:0016222 (IDA): ACCEPT (structural subunit).
peptidyl-proline hydroxylation GO:0018401 (IDA acts_upstream): KEEP_AS_NON_CORE (process via complex).
protein heterodimerization GO:0046982 (IDA, MTTP): ACCEPT (MTTP structural subunit).
ER chaperone complex GO:0034663 / protein-containing complex GO:0032991: KEEP_AS_NON_CORE.
protein folding / protein folding in ER / response to ER stress: KEEP_AS_NON_CORE (process; PDI
MF is core). Actually protein folding in ER is fairly core for PDI — ACCEPT-ish but keep as MF is core.
integrin binding GO:0005178 (IPI/IEA), enzyme binding, complex binding: KEEP_AS_NON_CORE.
actin binding GO:0003779 (IPI ACTB): KEEP_AS_NON_CORE (cytoplasmic moonlighting pool).
cell-adhesion/spreading/T-cell migration/viral entry/IL signaling: KEEP_AS_NON_CORE (moonlighting/surface).
insulin processing: KEEP_AS_NON_CORE.
regulation of oxidative-stress apoptosis / cellular response to hypoxia (IMP 12095988 UBQLN1): KEEP_AS_NON_CORE.
ER / ER lumen / melanosome / plasma membrane / external side PM / ERGIC / focal adhesion /
cytoskeleton / lamellipodium / cytosol / extracellular / exosome: ACCEPT ER/ER-lumen primary;
others KEEP_AS_NON_CORE. Redundant Reactome ER-lumen TAS -> KEEP_AS_NON_CORE.
RNA binding HDA: KEEP_AS_NON_CORE.
protein binding IPI block: KEEP_AS_NON_CORE; MODIFY MTTP partners (P55157) to protein heterodimerization
or keep; MARK_AS_OVER_ANNOTATED the broad screens (32296183, 32814053).

Pn Notes

(P4HB-pn-notes.md)

P4HB PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: P07237
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-07b
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/P4HB/P4HB-ai-review.yaml
AIGR review HTML: present - genes/human/P4HB/P4HB-ai-review.html
Gene notes: present - genes/human/P4HB/P4HB-notes.md
GOA TSV: present - genes/human/P4HB/P4HB-goa.tsv
UniProt record: present - genes/human/P4HB/P4HB-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/P4HB.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/P4HB.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

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/core annotation action counts: ACCEPT: 25; KEEP_AS_NON_CORE: 72; MARK_AS_OVER_ANNOTATED: 1

PN Consistency Summary

Consistency: Notes, review YAML, and both PN mappings are consistent. P4HB is the prototypical PDI: review ACCEPTs GO:0003756 (EXP/IDA/IEA, the canonical core MF) and documents its dual structural-subunit roles (P4H beta-subunit; MTTP). No contradiction.
PN story / NEW pressure: Row 1 GO:0003756 (OLS-verified) is already_in_goa_exact and ACCEPTed — captured. Row 2 GO:0032964 collagen biosynthetic process (OLS-verified real) is flagged new_to_goa. The review captures the collagen role via the prolyl-4-hydroxylase axis: GO:0004656 procollagen-proline 4-dioxygenase activity (contributes_to, IDA/TAS), GO:0016222 procollagen-proline 4-dioxygenase complex (part_of), GO:0018401 peptidyl-proline hydroxylation. These are more precise/mechanistic than GO:0032964 (a broad biosynthetic-process umbrella). So the PN's collagen story is biologically real and already mechanistically represented; GO:0032964 itself is a defensible (verified) but broader process-level addition. Conclusion: collagen role already captured at finer granularity; GO:0032964 is a legitimate-but-broader ADD, not strictly needed.
Evidence alignment: PN dossier lists no reference titles; alignment is by biology. Review collagen evidence (PMID:7753822, PMID:2846539, both GOA-anchored to GO:0004656/GO:0016222) and PDI evidence (PMID:15720785, 21091435, 32149426) are reviewer-supplied; no shared citation list to compare.
Verdict: Consistent; PDI core validated; collagen role real but already captured via finer P4H-complex terms, making GO:0032964 a broader optional addition. Recommended edits: [MAP] consider downgrading the ER-collagen-processing leaf projection (GO:0032964) to context/non-propagating for P4HB (it acts as the non-catalytic structural beta-subunit; the review's GO:0004656 contributes_to + GO:0016222 part_of are the more accurate, already-present representation).

Full Consistency Review

UniProt: P07237 · batch: proteostasis-batch-2026-06-07b · review status: COMPLETE
PN placement: 2 rows — (1) ER proteostasis|Folding enzyme|Protein disulfide isomerases; (2) ER proteostasis|Maturation and folding of specific substrates|ER collagen processing and folding. PN-node mapping: PDI group=mapped→GO:0003756 protein disulfide isomerase activity (already_in_goa_exact); ER-collagen group=mapped→GO:0032964 collagen biosynthetic process (new_to_goa); classes/branch=no_mapping.
Consistency: Notes, review YAML, and both PN mappings are consistent. P4HB is the prototypical PDI: review ACCEPTs GO:0003756 (EXP/IDA/IEA, the canonical core MF) and documents its dual structural-subunit roles (P4H beta-subunit; MTTP). No contradiction.
PN story / NEW pressure: Row 1 GO:0003756 (OLS-verified) is already_in_goa_exact and ACCEPTed — captured. Row 2 GO:0032964 collagen biosynthetic process (OLS-verified real) is flagged new_to_goa. The review captures the collagen role via the prolyl-4-hydroxylase axis: GO:0004656 procollagen-proline 4-dioxygenase activity (contributes_to, IDA/TAS), GO:0016222 procollagen-proline 4-dioxygenase complex (part_of), GO:0018401 peptidyl-proline hydroxylation. These are more precise/mechanistic than GO:0032964 (a broad biosynthetic-process umbrella). So the PN's collagen story is biologically real and already mechanistically represented; GO:0032964 itself is a defensible (verified) but broader process-level addition. Conclusion: collagen role already captured at finer granularity; GO:0032964 is a legitimate-but-broader ADD, not strictly needed.
Mapping strategy: Group-level GO:0003756 is the cleanest catalytic-family target (correctly already_in_goa_exact, matching AGR2/ERO1A/ERO1B/ERP27 siblings under the same node — but see the oxidase/non-catalytic caveats for those genes). For the collagen row, GO:0032964 is broader than the review's P4H-complex terms; per the TOMM20/HSPA8/RAB7A "broader-than-review" precedent it risks over-reaching the process when the review's structural-subunit framing (P4HB contributes_to, does not catalyze) is the more accurate model. Prefer the review's GO:0004656/GO:0016222 representation.
Evidence alignment: PN dossier lists no reference titles; alignment is by biology. Review collagen evidence (PMID:7753822, PMID:2846539, both GOA-anchored to GO:0004656/GO:0016222) and PDI evidence (PMID:15720785, 21091435, 32149426) are reviewer-supplied; no shared citation list to compare.
Verdict: Consistent; PDI core validated; collagen role real but already captured via finer P4H-complex terms, making GO:0032964 a broader optional addition. Recommended edits: [MAP] consider downgrading the ER-collagen-processing leaf projection (GO:0032964) to context/non-propagating for P4HB (it acts as the non-catalytic structural beta-subunit; the review's GO:0004656 contributes_to + GO:0016222 part_of are the more accurate, already-present representation).

PN Dossier Context

review_batch: proteostasis-batch-2026-06-07b
review_yaml: genes/human/P4HB/P4HB-ai-review.yaml
PN workbook rows: 2

PN row 1: ER proteostasis | Folding enzyme | Protein disulfide isomerases

UniProt: P07237
In branches: ER
PN-node mapping records (path + ancestors):
- [group] ER proteostasis|Folding enzyme|Protein disulfide isomerases
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0003756 protein disulfide isomerase activity]
  rationale: This PN group captures the canonical ER protein-disulfide-isomerase folding enzymes. GO protein disulfide isomerase activity is the cleanest propagation target for the catalytically active family members.
- [class] ER proteostasis|Folding enzyme
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
- [branch] ER proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

PN row 2: ER proteostasis | Maturation and folding of specific substrates | ER collagen processing and folding

UniProt: P07237
In branches: ER
PN-node mapping records (path + ancestors):
- [group] ER proteostasis|Maturation and folding of specific substrates|ER collagen processing and folding
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0032964 collagen biosynthetic process]
  rationale: This PN group contains ER factors dedicated to collagen maturation, processing, and folding. Collagen biosynthetic process captures the shared substrate-specific pathway context.
- [class] ER proteostasis|Maturation and folding of specific substrates
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
- [branch] ER proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (2)

GO:0003756 protein disulfide isomerase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=ER proteostasis|Folding enzyme|Protein disulfide isomerases
GO:0032964 collagen biosynthetic process | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Maturation and folding of specific substrates|ER collagen processing and folding

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

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.

P4HB

Gene Description

Existing Annotations Review

Core Functions

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).

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.

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.

Redox-dependent molecular chaperone that (at high concentration, following FAM20C phosphorylation) suppresses aggregation of misfolded proteins and regulates the UPR sensor ERN1/IRE1A.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

P4HB (PDI / PDIA1) research notes

Core multifunctional biology (well-established)

Subcellular location

Action plan

Pn Notes

P4HB PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: ER proteostasis | Folding enzyme | Protein disulfide isomerases

PN row 2: ER proteostasis | Maturation and folding of specific substrates | ER collagen processing and folding

Projected GO annotations (2)

Note

📄 View Raw YAML