id: O95881 gene_symbol: TXNDC12 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- TXNDC12 (Thioredoxin domain-containing protein 12; also known as ERp18, ERp19, ERp16, and hTLP19) is a small (172 aa precursor; 146 aa mature) soluble thioredoxin- superfamily oxidoreductase resident in the endoplasmic reticulum lumen. After cleavage of an N-terminal signal peptide it is retained in the ER via a C-terminal EDEL motif. It comprises a single thioredoxin-like fold carrying an unusual CGAC redox-active active-site motif (catalytic cysteines Cys66/Cys69) with a redox potential (about -165 mV) within the range of the ER, allowing it to catalyze the formation, reduction, and isomerization of disulfide bonds in client/substrate proteins. TXNDC12 thus acts early in oxidative protein folding in the ER, promoting native disulfide bond formation, and contributes to cellular defense against prolonged ER stress, where its catalytic activity attenuates ER-stress-induced apoptosis. It is widely expressed. existing_annotations: - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: >- Phylogenetic (IBA) assignment of ER localization, consistent with the experimentally determined ER-lumen localization and the protein's EDEL retention motif. action: ACCEPT reason: >- Correct compartment; TXNDC12 is an ER-resident oxidoreductase acting in oxidative protein folding in the ER. supported_by: - reference_id: file:human/TXNDC12/TXNDC12-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen' - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: >- Electronic assignment of ER lumen localization, redundant with and consistent with the experimental IDA annotation and the curated UniProt subcellular location. action: ACCEPT reason: >- Correct site of action; the mature soluble protein is retained in the ER lumen via its EDEL motif. supported_by: - reference_id: file:human/TXNDC12/TXNDC12-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen' - term: id: GO:0019153 label: protein-disulfide reductase (glutathione) activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: >- Electronic assignment of the glutathione-dependent protein-disulfide reductase activity (EC 1.8.4.2), redundant with the experimental IDA annotation from the ERp18 characterization. action: ACCEPT reason: >- Correct core molecular function; corresponds to the curated EC 1.8.4.2 and the CGAC active-site redox chemistry. supported_by: - reference_id: file:human/TXNDC12/TXNDC12-uniprot.txt supporting_text: EC=1.8.4.2 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: >- IntAct capture from a proteome-scale human interactome map. Bare protein binding is uninformative relative to the established oxidoreductase function. action: KEEP_AS_NON_CORE reason: >- High-throughput interactome data; per guidelines bare protein binding is not elevated to a core function. supported_by: - reference_id: file:human/TXNDC12/TXNDC12-uniprot.txt supporting_text: 'O95881; O43765: SGTA; NbExp=3; IntAct=EBI-2564581, EBI-347996;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31515488 qualifier: enables review: summary: >- IntAct capture from a variant-interactome screen. Uninformative bare protein binding. action: KEEP_AS_NON_CORE reason: >- High-throughput interactome data; not elevated to core per guidelines. supported_by: - reference_id: file:human/TXNDC12/TXNDC12-uniprot.txt supporting_text: 'O95881; Q9UMX0: UBQLN1; NbExp=4; IntAct=EBI-2564581, EBI-741480;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: >- IntAct capture from the HuRI binary interactome. Uninformative bare protein binding. action: KEEP_AS_NON_CORE reason: >- High-throughput interactome data; not elevated to core per guidelines. supported_by: - reference_id: file:human/TXNDC12/TXNDC12-uniprot.txt supporting_text: 'O95881; P49069: CAMLG; NbExp=5; IntAct=EBI-2564581, EBI-1748958;' - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: >- Ortholog-based electronic transfer of ER localization, consistent with the experimental ER-lumen localization. action: ACCEPT reason: >- Correct compartment; redundant with the IDA/IBA ER annotations. supported_by: - reference_id: file:human/TXNDC12/TXNDC12-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen' - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: IDA original_reference_id: PMID:12761212 qualifier: part_of review: summary: >- Direct experimental demonstration that ERp18 (TXNDC12) is located in the endoplasmic reticulum, consistent with its EDEL ER-retention motif. action: ACCEPT reason: >- Experimentally supported ER-lumen localization; the curated site of action. supported_by: - reference_id: PMID:12761212 supporting_text: We show that ERp18 is located in the endoplasmic reticulum - term: id: GO:0019153 label: protein-disulfide reductase (glutathione) activity evidence_type: IDA original_reference_id: PMID:12761212 qualifier: enables review: summary: >- Direct biochemical demonstration that ERp18 (TXNDC12) has peptide thiol-disulfide oxidase activity dependent on both active-site cysteines (CGAC motif), the basis of EC 1.8.4.2. This is a core molecular function. action: ACCEPT reason: >- Core, experimentally supported molecular function; mutation of either active-site cysteine abolishes activity. supported_by: - reference_id: PMID:12761212 supporting_text: >- in vitro ERp18 possesses significant peptide thiol-disulfide oxidase activity, which is dependent on the presence of both active site cysteine residues. - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: IDA original_reference_id: PMID:18628206 qualifier: located_in review: summary: >- Direct evidence that the mature protein (ERp16/TXNDC12) is localized in the lumen of the ER, consistent with its EDEL retention sequence. action: ACCEPT reason: >- Experimentally supported ER-lumen localization. supported_by: - reference_id: PMID:18628206 supporting_text: >- a COOH-terminal endoplasmic reticulum (ER) retention sequence (EDEL) - term: id: GO:0015035 label: protein-disulfide reductase activity evidence_type: IDA original_reference_id: PMID:18628206 qualifier: enables review: summary: >- Direct biochemical demonstration that ERp16/TXNDC12 is a thiol-disulfide oxidoreductase catalyzing the formation, reduction, and isomerization of disulfide bonds via its CGAC active site. This is the core molecular function. action: ACCEPT reason: >- Core, experimentally supported molecular function; the broad protein-disulfide reductase/oxidoreductase activity is the protein's defining biochemical role. supported_by: - reference_id: PMID:18628206 supporting_text: >- it catalyzed the formation, reduction, and isomerization of disulfide bonds, with the unusual CGAC active site motif being responsible for these activities - term: id: GO:1902236 label: negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway evidence_type: IDA original_reference_id: PMID:18628206 qualifier: acts_upstream_of_or_within review: summary: >- Overexpression of ERp16/TXNDC12 inhibited ER-stress-induced apoptosis whereas a catalytically inactive mutant or knockdown potentiated it, demonstrating a catalysis- dependent protective role against prolonged ER stress. This is a downstream physiological consequence of its redox-folding activity rather than its primary biochemical function. action: KEEP_AS_NON_CORE reason: >- Well supported experimentally (PMID:18628206) but represents a downstream/physiological output of the core oxidoreductase activity; retained as non-core. supported_by: - reference_id: PMID:18628206 supporting_text: >- Expression of ERp16 in HeLa cells inhibited the induction of apoptosis by agents that elicit ER stress, including brefeldin A, tunicamycin, and dithiothreitol. core_functions: - description: >- ER-luminal thiol-disulfide oxidoreductase that, via its CGAC active-site motif (Cys66/Cys69), catalyzes formation, reduction, and isomerization of disulfide bonds in client proteins, contributing to oxidative protein folding in the endoplasmic reticulum. molecular_function: id: GO:0015035 label: protein-disulfide reductase activity locations: - id: GO:0005788 label: endoplasmic reticulum lumen supported_by: - reference_id: PMID:18628206 supporting_text: >- it catalyzed the formation, reduction, and isomerization of disulfide bonds, with the unusual CGAC active site motif being responsible for these activities - reference_id: PMID:12761212 supporting_text: >- in vitro ERp18 possesses significant peptide thiol-disulfide oxidase activity, which is dependent on the presence of both active site cysteine residues. proposed_new_terms: [] references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:12761212 title: Functional characterization of ERp18, a new endoplasmic reticulum-located thioredoxin superfamily member. findings: - statement: >- ERp18 (TXNDC12) is an ER-located, PDI-related protein with a single catalytic thioredoxin domain bearing an unusual CGAC active-site motif and possesses peptide thiol-disulfide oxidase activity dependent on both active-site cysteines. reference_section_type: ABSTRACT full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Original functional characterization of ERp18/TXNDC12; basis of EC 1.8.4.2 and the C66/C69 active-site annotations. Cached entry is abstract-only. - id: PMID:18628206 title: 'ERp16, an endoplasmic reticulum-resident thiol-disulfide oxidoreductase: biochemical properties and role in apoptosis induced by endoplasmic reticulum stress.' findings: - statement: >- ERp16 (the same protein as ERp18/ERp19/hTLP19/TXNDC12) is an ER-lumen thiol-disulfide oxidoreductase (redox potential about -165 mV) that catalyzes formation, reduction, and isomerization of disulfide bonds via its CGAC motif. reference_section_type: ABSTRACT - statement: >- Catalytically active TXNDC12 protects HeLa cells against ER-stress-induced apoptosis, whereas a catalytically dead mutant or knockdown potentiates it, indicating a catalysis-dependent role in defense against prolonged ER stress. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Full-text cached; confirms the same gene under the ERp16 alias and supports both the core oxidoreductase function and the anti-apoptotic role under ER stress. - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: >- Proteome-scale interactome; source of a high-throughput protein binding capture. - id: PMID:31515488 title: Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: >- Variant-interactome screen; source of a high-throughput protein binding capture. - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: >- HuRI binary interactome; source of a high-throughput protein binding capture. - id: PMID:39696500 title: A novel role for protein disulfide isomerase ERp18 in venous thrombosis. findings: - statement: >- ERp18 (TXNDC12) enhances venous thrombosis: ERp18-knockout mice develop significantly less thrombosis in an inferior vena cava stenosis model, and this pro-thrombotic role is dependent on its enzymatic activity (the inactive CGAC-to-SGAS mutant fails to support thrombosis). ERp18 is detected in endothelial cells, leukocytes and platelets and its deficiency lowers vWF at the thrombus site, implicating ERp18 in regulating vWF release. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- PubMed-verified (PMID:39696500, DOI:10.1186/s12959-024-00678-5). Gene-specific 2024 primary study establishing a context-dependent extracellular/vascular role for TXNDC12/ERp18 in venous thrombosis and reconfirming that the CGAC active site is required for activity (CGAC-to-SGAS abolishes function). The thrombosis/vWF role is a non-core physiological output; the catalytic-dependence data corroborate the core oxidoreductase function. Full text not cached, so no verbatim supporting_text added to annotations. - id: file:human/TXNDC12/TXNDC12-uniprot.txt title: UniProt entry O95881 (TXD12_HUMAN), Thioredoxin domain-containing protein 12 findings: - statement: >- Protein-disulfide reductase (EC 1.8.4.2) of the ER lumen with a single thioredoxin domain, redox-active C66/C69, EDEL ER-retention motif; promotes disulfide bond formation in client proteins. reference_section_type: OTHER suggested_questions: - question: >- What are the endogenous physiological substrates whose native disulfide bonds depend on TXNDC12, and does it act redundantly with other ER PDI-family oxidoreductases? - question: >- How does the unusual CGAC active-site motif tune TXNDC12 between oxidase, reductase, and isomerase activities relative to canonical CXXC PDI enzymes? suggested_experiments: - description: >- Identify TXNDC12 substrates by trapping mixed-disulfide intermediates with active-site cysteine-trapping mutants followed by mass spectrometry in human cells. - description: >- Test whether TXNDC12 depletion sensitizes cells to ER-stress-induced apoptosis and whether re-expression of wild-type but not CGAC-mutant protein rescues, to confirm the catalysis- dependent cytoprotective role.