EPS1 encodes an endoplasmic-reticulum membrane protein of the protein disulfide isomerase family. The best-supported role of Eps1 is ER quality control: it recognizes and retains aberrant secretory-pathway membrane substrates, especially Pma1-D378N, and promotes their delivery to the Doa10-linked ER-associated degradation pathway. Eps1 has thioredoxin-like CXXC active-site motifs and experimentally reported reductase/chaperone activities, but its in vivo specificity is more accurately described as membrane-bound ERAD substrate recognition and quality-control routing than as general protein folding throughout the secretome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003756 protein disulfide isomerase activity | IBA GO_REF:0000033 | ACCEPT | Summary: The PANTHER/IBA transfer is consistent with Eps1 membership in the PDI family and with direct yeast studies showing thioredoxin-like CPHC/CDKC motifs required for ER quality-control substrate handling. Eps1 is not a broad soluble foldase like Pdi1, but protein disulfide isomerase-family oxidoreductase activity is a defensible molecular-function annotation. Reason: Retain as a family-consistent molecular function, while interpreting it in the narrower context of Eps1-dependent ER quality control. Supporting Evidence: PMID:12881414 Eps1 has two thioredoxin-like domains containing a CPHC and a CDKC active site. file:yeast/EPS1/EPS1-deep-research-falcon.md Falcon deep research synthesizes EPS1 as an ER membrane PDI-family factor for ER quality control and ERAD substrate recognition. |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: Eps1 acts in the ER and the IBA localization is supported by direct localization and functional studies. More specific ER membrane annotations are also present, but this broader ER term is correct. Reason: Eps1 is an ER-localized quality-control factor. Supporting Evidence: PMID:10545109 Eps1 is a novel membrane protein belonging to the protein disulfide isomerase (PDI) family, and Eps1 co-localizes with Pma1-D378N in the ER. |
| GO:0006457 protein folding | IBA GO_REF:0000033 | ACCEPT | Summary: The protein folding annotation is acceptable for a PDI-family ER chaperone/quality-control protein, but it should be interpreted as substrate quality control and ERAD-linked folding surveillance rather than broad essential oxidative folding. Reason: Eps1 has experimentally supported membrane-bound chaperone activity in ER quality control. Supporting Evidence: PMID:10545109 Because Eps1 is required for retention and degradation of Pma1-D378N, we propose a model in which Eps1 acts as a novel membrane-bound chaperone in ER quality control. |
| GO:0003756 protein disulfide isomerase activity | IEA GO_REF:0000003 | ACCEPT | Summary: The EC-based IEA annotation is consistent with Eps1's PDI-family thioredoxin-like active-site motifs and with experimental annotation of PDI-related activity. It is less informative than the ERAD-specific process annotation but not wrong. Reason: Retain as a valid but broad enzymatic-family annotation. Supporting Evidence: PMID:12881414 Recognition of Pma1-D378N by the ERAD pathway is dependent on Eps1, a transmembrane member of the protein disulfide isomerase (PDI) oxidoreductase family. |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | REMOVE | Summary: The ARBA-derived cytoplasm annotation is not supported by the curated yeast evidence. Eps1 is a precursor with an ER signal sequence and a single-pass ER membrane topology; its quality-control function is in the ER, not the cytoplasm. Reason: Cytoplasm misrepresents the experimentally supported ER membrane localization and should not be retained. Supporting Evidence: PMID:10545109 Eps1 is a novel membrane protein belonging to the protein disulfide isomerase (PDI) family, and Eps1 co-localizes with Pma1-D378N in the ER. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: This is the most accurate cellular-component annotation for Eps1. Direct studies show it is an integral ER membrane protein, and the ER membrane is where it couples luminal substrate recognition to membrane ERAD machinery. Reason: Core localization for the active Eps1 protein. Supporting Evidence: PMID:10545109 Eps1 is a novel membrane protein belonging to the protein disulfide isomerase (PDI) family, and Eps1 co-localizes with Pma1-D378N in the ER. PMID:12881414 Recognition of Pma1-D378N by the ERAD pathway is dependent on Eps1, a transmembrane member of the protein disulfide isomerase (PDI) oxidoreductase family. |
| GO:0012505 endomembrane system | IEA GO_REF:0000117 | MODIFY | Summary: Endomembrane system is true but unnecessarily broad for Eps1. The same evidence should resolve to endoplasmic reticulum membrane, which is directly supported. Reason: Replace broad ARBA localization with the specific experimentally supported ER membrane term. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:10545109 Eps1 is a novel membrane protein belonging to the protein disulfide isomerase (PDI) family, and Eps1 co-localizes with Pma1-D378N in the ER. |
| GO:0016853 isomerase activity | IEA GO_REF:0000043 | MODIFY | Summary: Generic isomerase activity loses the important chemistry and family context. Eps1 should be represented by protein disulfide isomerase activity rather than the broad parent term. Reason: A more specific child term is already supported for Eps1. Proposed replacements: protein disulfide isomerase activity Supporting Evidence: PMID:12881414 Recognition of Pma1-D378N by the ERAD pathway is dependent on Eps1, a transmembrane member of the protein disulfide isomerase (PDI) oxidoreductase family. |
| GO:0036503 ERAD pathway | IMP PMID:12881414 Substrate recognition in ER-associated degradation mediated ... | ACCEPT | Summary: This is the best biological-process annotation for Eps1. Loss of EPS1 impairs recognition and degradation of Pma1-D378N and other ERAD substrates, and eps1Delta cells show genetic and UPR evidence of ERAD stress. Reason: Core process supported by direct mutant and substrate-recognition evidence. Supporting Evidence: PMID:12881414 Genetic interactions with other mutants of the ERAD machinery and induction of the unfolded protein response in eps1Delta cells support a general role for Eps1 as a recognition component of the ERAD pathway. |
| GO:0005515 protein binding | IPI PMID:16002399 Interactions among yeast protein-disulfide isomerase protein... | MARK AS OVER ANNOTATED | Summary: Eps1 interactions with Pdi1, Eug1, Mpd1, Kar2 and Cne1-related ER chaperone systems are biologically relevant, but the generic protein binding term is not informative and should not be presented as a standalone molecular function. Reason: Specific oxidoreductase/chaperone and ERAD substrate-recognition annotations better capture Eps1 biology than GO:0005515. Supporting Evidence: PMID:16002399 Eps1p interacts with Pdi1p, Eug1p, Mpd1p, and Kar2p with dissociation constants (KD) in the range of 10(-7) to 10(-6). |
| GO:0019153 protein-disulfide reductase (glutathione) activity | IDA PMID:16002399 Interactions among yeast protein-disulfide isomerase protein... | REMOVE | Summary: The cited paper reports undetectable Eps1p protein-disulfide reductase activity in the glutathione-dependent assay used for this annotation. Reason: The original IDA source provides direct evidence against detectable Eps1p activity for this specific glutathione-dependent reductase term. Eps1 retains PDI-family/chaperone annotations where supported, but this narrower reductase annotation should be removed. Supporting Evidence: PMID:16002399 found that Mpd1p, Mpd2, and Eug1p exhibit activities of 13.8, 16.0, and 2.16%, respectively, compared with Pdi1p and that activity for Eps1p is undetectable. |
| GO:0003756 protein disulfide isomerase activity | IMP PMID:11157982 Functional differences in yeast protein disulfide isomerases... | ACCEPT | Summary: The genetic evidence from yeast PDI homolog studies supports retaining a PDI activity annotation for EPS1, while noting that Eps1 is not functionally interchangeable with Pdi1 and its main in vivo role is ER quality control. Reason: Valid PDI-family activity annotation, interpreted with functional specificity. Supporting Evidence: PMID:11157982 The Saccharomyces cerevisiae genome, however, contains four other nonessential genes with homology to PDI1: MPD1, MPD2, EUG1, and EPS1. |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:10545109 Eps1, a novel PDI-related protein involved in ER quality con... | ACCEPT | Summary: Direct assay evidence supports ER membrane localization. This is a core cellular component for Eps1. Reason: Directly supported ER membrane localization. Supporting Evidence: PMID:10545109 Eps1 is a novel membrane protein belonging to the protein disulfide isomerase (PDI) family, and Eps1 co-localizes with Pma1-D378N in the ER. |
| GO:0006621 protein retention in ER lumen | IMP PMID:10545109 Eps1, a novel PDI-related protein involved in ER quality con... | MODIFY | Summary: EPS1 is required for ER retention and degradation of the misfolded membrane protein Pma1-D378N, but the current term is misleading because Pma1 is not an ER-lumen resident protein and the same study reports that normal retention of resident ER proteins Shr3 and Kar2 is not perturbed. ERAD pathway is the better biological-process annotation. Reason: Replace an assay-specific and lumen-biased retention term with the mechanistically accurate ERAD pathway term. Proposed replacements: ERAD pathway Supporting Evidence: PMID:10545109 In an eps1 mutant, both mutant and wild-type Pma1 molecules are allowed to travel to the plasma membrane; however, normal retention of resident ER proteins Shr3 and Kar2 is not perturbed. |
| GO:0051082 unfolded protein binding | IDA PMID:16002399 Interactions among yeast protein-disulfide isomerase protein... | ACCEPT | Summary: Unlike the mitochondrial assembly-factor examples where unfolded protein binding overstates the evidence, Eps1 has a documented ER chaperone/quality control role and physically engages aberrant secretory-pathway substrates. This term is still broad, but it is defensible for Eps1 as a membrane-bound chaperone. Reason: Retain as a valid chaperone-related molecular function, secondary to the more specific PDI redox and ERAD-process annotations. Supporting Evidence: PMID:16002399 co-chaperone activities were completely suppressed in Eps1p-Pdi1p and Eps1p-Mpd1p complexes, although only Eps1p and Pdi1p have chaperone activity. |
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Download this section (compressed HTML)Q: Should EPS1 retain a broad unfolded protein binding annotation, or should GO curation represent its chaperone role only through PDI redox activity and ERAD substrate-recognition/process terms?
Suggested experts: Wang Q, Chang A
Experiment: Reconstitute Eps1-dependent recognition of Pma1-D378N and additional ERAD substrates using active-site and membrane-anchor mutants, then measure substrate binding, Doa10 handoff, and degradation kinetics.
Hypothesis: Eps1 active-site cysteine chemistry is required for substrate recognition rather than for broad oxidative folding.
Type: ERAD substrate-recognition assay
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