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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment of ER localization, consistent with the experimentally determined ER-lumen localization and the protein's EDEL retention motif. Reason: Correct compartment; TXNDC12 is an ER-resident oxidoreductase acting in oxidative protein folding in the ER. Supporting Evidence: file:human/TXNDC12/TXNDC12-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of ER lumen localization, redundant with and consistent with the experimental IDA annotation and the curated UniProt subcellular location. Reason: Correct site of action; the mature soluble protein is retained in the ER lumen via its EDEL motif. Supporting Evidence: file:human/TXNDC12/TXNDC12-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0019153 protein-disulfide reductase (glutathione) activity | IEA GO_REF:0000120 | ACCEPT | 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. Reason: Correct core molecular function; corresponds to the curated EC 1.8.4.2 and the CGAC active-site redox chemistry. Supporting Evidence: file:human/TXNDC12/TXNDC12-uniprot.txt EC=1.8.4.2 |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: IntAct capture from a proteome-scale human interactome map. Bare protein binding is uninformative relative to the established oxidoreductase function. Reason: High-throughput interactome data; per guidelines bare protein binding is not elevated to a core function. Supporting Evidence: file:human/TXNDC12/TXNDC12-uniprot.txt O95881; O43765: SGTA; NbExp=3; IntAct=EBI-2564581, EBI-347996; |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | KEEP AS NON CORE | Summary: IntAct capture from a variant-interactome screen. Uninformative bare protein binding. Reason: High-throughput interactome data; not elevated to core per guidelines. Supporting Evidence: file:human/TXNDC12/TXNDC12-uniprot.txt O95881; Q9UMX0: UBQLN1; NbExp=4; IntAct=EBI-2564581, EBI-741480; |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: IntAct capture from the HuRI binary interactome. Uninformative bare protein binding. Reason: High-throughput interactome data; not elevated to core per guidelines. Supporting Evidence: file:human/TXNDC12/TXNDC12-uniprot.txt O95881; P49069: CAMLG; NbExp=5; IntAct=EBI-2564581, EBI-1748958; |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog-based electronic transfer of ER localization, consistent with the experimental ER-lumen localization. Reason: Correct compartment; redundant with the IDA/IBA ER annotations. Supporting Evidence: file:human/TXNDC12/TXNDC12-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | IDA PMID:12761212 Functional characterization of ERp18, a new endoplasmic reti... | ACCEPT | Summary: Direct experimental demonstration that ERp18 (TXNDC12) is located in the endoplasmic reticulum, consistent with its EDEL ER-retention motif. Reason: Experimentally supported ER-lumen localization; the curated site of action. Supporting Evidence: PMID:12761212 We show that ERp18 is located in the endoplasmic reticulum |
| GO:0019153 protein-disulfide reductase (glutathione) activity | IDA PMID:12761212 Functional characterization of ERp18, a new endoplasmic reti... | ACCEPT | 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. Reason: Core, experimentally supported molecular function; mutation of either active-site cysteine abolishes activity. Supporting Evidence: PMID:12761212 in vitro ERp18 possesses significant peptide thiol-disulfide oxidase activity, which is dependent on the presence of both active site cysteine residues. |
| GO:0005788 endoplasmic reticulum lumen | IDA PMID:18628206 ERp16, an endoplasmic reticulum-resident thiol-disulfide oxi... | ACCEPT | Summary: Direct evidence that the mature protein (ERp16/TXNDC12) is localized in the lumen of the ER, consistent with its EDEL retention sequence. Reason: Experimentally supported ER-lumen localization. Supporting Evidence: PMID:18628206 a COOH-terminal endoplasmic reticulum (ER) retention sequence (EDEL) |
| GO:0015035 protein-disulfide reductase activity | IDA PMID:18628206 ERp16, an endoplasmic reticulum-resident thiol-disulfide oxi... | ACCEPT | 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. Reason: Core, experimentally supported molecular function; the broad protein-disulfide reductase/oxidoreductase activity is the protein's defining biochemical role. Supporting Evidence: PMID:18628206 it catalyzed the formation, reduction, and isomerization of disulfide bonds, with the unusual CGAC active site motif being responsible for these activities |
| GO:1902236 negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway | IDA PMID:18628206 ERp16, an endoplasmic reticulum-resident thiol-disulfide oxi... | KEEP AS NON CORE | 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. Reason: Well supported experimentally (PMID:18628206) but represents a downstream/physiological output of the core oxidoreductase activity; retained as non-core. Supporting Evidence: PMID:18628206 Expression of ERp16 in HeLa cells inhibited the induction of apoptosis by agents that elicit ER stress, including brefeldin A, tunicamycin, and dithiothreitol. |
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Download this section (compressed HTML)Q: What are the endogenous physiological substrates whose native disulfide bonds depend on TXNDC12, and does it act redundantly with other ER PDI-family oxidoreductases?
Q: How does the unusual CGAC active-site motif tune TXNDC12 between oxidase, reductase, and isomerase activities relative to canonical CXXC PDI enzymes?
Experiment: Identify TXNDC12 substrates by trapping mixed-disulfide intermediates with active-site cysteine-trapping mutants followed by mass spectrometry in human cells.
Experiment: 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.
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