ERP29 (endoplasmic reticulum resident protein 29; also called ERp28 and ERp31) is a soluble, ER-lumenal, homodimeric member of the protein disulfide isomerase (PDI) family that is catalytically redox-inactive - it has a thioredoxin-like fold but lacks the CXXC active-site motif and is not a disulfide isomerase. It functions as a non-catalytic escort/chaperone that assists the folding, processing and trafficking of secretory cargo in the ER, and is a component of a large ER chaperone multiprotein complex (containing BiP/HSPA5, GRP94/HSP90B1, PDI, the Hsp40 co-chaperone ERdj3/DNAJB11, cyclophilin B/PPIB, ERp72/PDIA4, UGGT1 and SDF2L1) that binds nascent, incompletely folded clients such as immunoglobulin heavy chains. It is retained in the ER lumen by a C-terminal KEEL retention signal and is broadly expressed, especially in secretory tissues; pools have also been detected at the cell surface, in melanosomes and secreted. Beyond its core chaperone role it has been implicated in handling of specific cargo (e.g. thyroglobulin, connexins) and in toxin/virus membrane penetration, and in cell-context-specific signaling (p38 MAPK, gene expression and secretion control in cancer models).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: ERP29 is an ER-resident lumenal protein; the ER is its primary site of action. Reason: ER localization is well supported (retention signal, immunofluorescence, fractionation) and is the core compartment for ERP29's chaperone function. Supporting Evidence: file:human/ERP29/ERP29-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000002 | ACCEPT | Summary: Electronic ER localization, consistent with the IBA/IDA evidence. Reason: Correct compartment for this ER-resident chaperone. Supporting Evidence: file:human/ERP29/ERP29-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000120 | ACCEPT | Summary: ERP29 is a soluble ER-lumenal protein with a KEEL retention signal; the precise compartment. Reason: ER lumen is the documented, precise localization for this soluble chaperone. Supporting Evidence: file:human/ERP29/ERP29-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0009306 protein secretion | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: ERP29 participates in the processing and secretion of secretory proteins; a plausible downstream process of its chaperone role. Reason: ERP29 facilitates secretory-protein processing/trafficking, so a protein-secretion process annotation is reasonable but is a downstream consequence of its chaperone function rather than a direct molecular activity. Supporting Evidence: file:human/ERP29/ERP29-uniprot.txt Plays an important role in the processing of secretory proteins within the endoplasmic reticulum |
| GO:0042470 melanosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: ERP29 was identified by mass spectrometry in melanosome fractions; a secondary localization. Reason: A proteomics-detected secondary localization, peripheral to the core ER-lumenal chaperone function. Supporting Evidence: file:human/ERP29/ERP29-uniprot.txt Identified by mass spectrometry in melanosome fractions |
| GO:0005515 protein binding | IPI PMID:23864651 The identification of novel proteins that interact with the ... | KEEP AS NON CORE | Summary: Interaction with the GLP-1 receptor (GLP1R/P43220) identified in a screen for GLP1R-interacting proteins. The bare protein binding term is uninformative. Reason: A specific interaction (GLP1R) consistent with ERP29 handling secretory/membrane clients, but the generic protein binding term is uninformative and not core. Supporting Evidence: file:human/ERP29/ERP29-uniprot.txt P30040; P43220: GLP1R; NbExp=2; IntAct=EBI-946830, EBI-7466542; |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Reference binary interactome capturing many ERP29 interactions (e.g. SGTA, SGTB, TMBIM6, UBQLN1/2). Bare protein binding is uninformative. Reason: High-throughput binary interactions; the generic protein binding term is uninformative and not part of the core function. Supporting Evidence: file:human/ERP29/ERP29-uniprot.txt P30040; O43765: SGTA; NbExp=3; IntAct=EBI-946830, EBI-347996; |
| GO:0005576 extracellular region | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Extracellular/secreted pool inferred from the rat ortholog; peripheral to the ER chaperone role. Reason: A secreted pool is reported (and ERP29 is detected at the cell surface), but this is secondary to its core ER-lumenal localization. Supporting Evidence: file:human/ERP29/ERP29-uniprot.txt Melanosome. |
| GO:0005790 smooth endoplasmic reticulum | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Smooth-ER localization inferred from the rat ortholog; a sub-compartment refinement of the ER localization. Reason: A plausible ER sub-compartment annotation transferred by similarity; subsumed by the core ER/ER-lumen localization. Supporting Evidence: file:human/ERP29/ERP29-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0006888 endoplasmic reticulum to Golgi vesicle-mediated transport | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ER-to-Golgi transport role inferred from the rat ortholog; consistent with ERP29's role in secretory-cargo trafficking. The falcon deep research corroborates a role in the early secretory pathway, with ERP29 cycling between ER and Golgi via the KDEL receptor (its weaker KEEL retention variant) to escort clients such as ENaC. Reason: A plausible downstream trafficking process inferred by similarity; non-core relative to the chaperone molecular function. The falcon deep research provides additional (unverified) support for dynamic ER-to-Golgi cycling via the KDEL receptor and a role in client forward trafficking, reinforcing the biological plausibility of this process annotation. Supporting Evidence: file:human/ERP29/ERP29-uniprot.txt Plays an important role in the processing of secretory proteins within the endoplasmic reticulum file:human/ERP29/ERP29-deep-research-falcon.md dynamic cycling between the ER and Golgi apparatus via interactions with the KDEL receptor |
| GO:0009725 response to hormone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: A broad 'response to hormone' process inferred from the rat ortholog; vague and not characteristic of ERP29's molecular function. Reason: An unspecific, by-similarity process annotation with no direct human evidence and no clear connection to ERP29's chaperone function; over-annotated. Supporting Evidence: file:human/ERP29/ERP29-goa.tsv GO:0009725 |
| GO:0009986 cell surface | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cell-surface localization inferred from the mouse ortholog; corroborated by direct evidence in platelets, but secondary to the ER role. Reason: A genuine but minor surface pool (also IDA in platelets); peripheral to ERP29's core ER-lumenal chaperone function. Supporting Evidence: file:human/ERP29/ERP29-uniprot.txt Melanosome. |
| GO:0042803 protein homodimerization activity | IEA GO_REF:0000107 | ACCEPT | Summary: ERP29 functions as a homodimer; homodimerization is a genuine structural property documented by UniProt and crystal structures. Reason: ERP29 is a well-documented homodimer; homodimerization activity is correct, though it is structural rather than the principal client-facing function. Supporting Evidence: file:human/ERP29/ERP29-uniprot.txt SUBUNIT: Homodimer. |
| GO:0051087 protein-folding chaperone binding | IEA GO_REF:0000107 | ACCEPT | Summary: ERP29 binds molecular chaperones as part of a large ER chaperone complex (BiP, GRP94, PDI, ERdj3, cyclophilin B, ERp72, etc.) and, per the falcon deep research, is recruited to the calnexin/calreticulin (CNX/CRT) lectin-chaperone cycle, with its C-terminal D domain serving as the binding interface for the CNX/CRT P domains; chaperone binding is central to its escort function. Reason: ERP29's participation in the ER chaperone multiprotein complex is experimentally documented; protein-folding chaperone binding is an informative, core molecular function. The falcon deep research adds a specific mechanistic basis - ERP29 is recruited as a function-specific co-chaperone within the calnexin/calreticulin cycle via direct binding of its D domain to the CNX/CRT P domains - consistent with this chaperone-binding annotation (these CNX/CRT-cycle citations were not independently verified against cached publications). Supporting Evidence: PMID:12475965 large endoplasmic reticulum (ER)-localized multiprotein complex that is comprised of the molecular chaperones BiP file:human/ERP29/ERP29-deep-research-falcon.md C-terminal D domain serves as the principal binding interface for lectin chaperones in the calnexin/calreticulin system |
| GO:1902235 regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A role in regulating ER-stress-induced apoptosis inferred from the mouse ortholog; consistent with ERP29's ER-stress-related functions but indirect. The falcon deep research reports human-cell evidence (RPE cells) that ERP29 overexpression raises protective stress proteins (GRP78, p58IPK, Nrf2) and lowers pro-apoptotic CHOP, supporting a protective modulation of ER-stress-induced apoptotic signaling. Reason: A plausible context-specific process inferred by similarity; non-core relative to the chaperone molecular function. The falcon deep research adds (unverified) supportive evidence that ERP29 attenuates ER stress and shifts the balance away from CHOP-driven apoptosis, consistent with this regulatory annotation though still peripheral to its core chaperone-binding function. Supporting Evidence: file:human/ERP29/ERP29-uniprot.txt Plays an important role in the processing of secretory proteins within the endoplasmic reticulum file:human/ERP29/ERP29-deep-research-falcon.md increased levels of protective stress response proteins including GRP78, p58IPK, and Nrf2, while reducing pro-apoptotic markers phospho-eIF2Ξ± and CHOP |
| GO:0043410 positive regulation of MAPK cascade | IDA PMID:22064321 ERp29 induces breast cancer cell growth arrest and survival ... | KEEP AS NON CORE | Summary: In breast cancer cells, ERP29 overexpression activates p38 MAPK and induces growth arrest; a cell-context-specific signaling effect. Reason: Documented in a cancer-overexpression model; a specialized downstream signaling effect rather than ERP29's core ER chaperone function. Supporting Evidence: PMID:22064321 ERp29-induced cancer cell growth arrest is modulated by the interplay between the concomitant phosphorylation of p38 |
| GO:0005790 smooth endoplasmic reticulum | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS smooth-ER localization (rat ortholog); a sub-compartment refinement. Reason: Redundant with the IEA smooth-ER annotation; subsumed by the core ER/ER-lumen localization. Supporting Evidence: file:human/ERP29/ERP29-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0051087 protein-folding chaperone binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS protein-folding chaperone binding (rat ortholog), consistent with ERP29's role in the ER chaperone complex. Reason: Corroborates the experimentally supported chaperone-binding function (ER chaperone complex membership); an informative core molecular function. Supporting Evidence: PMID:12475965 large endoplasmic reticulum (ER)-localized multiprotein complex that is comprised of the molecular chaperones BiP |
| GO:0003756 protein disulfide isomerase activity | IKR NOT PMID:9738895 ERp28, a human endoplasmic-reticulum-lumenal protein, is a m... | ACCEPT | Summary: This is a NOT (negated) annotation - ERP29 does NOT have protein disulfide isomerase activity, because it lacks the CXXC thioredoxin-box motif. The negation is correct. Reason: Directly supported - ERP29 lacks the CXXC (CGHC) active-site motif and is not a disulfide isomerase; the NOT annotation correctly blocks transfer of isomerase activity. The falcon deep research independently affirms the redox-inactive, non-catalytic nature of ERP29 (lacks the CXXC catalytic motif; functions as a chaperone, not a catalyst). Supporting Evidence: PMID:9738895 member of the protein disulfide isomerase family but lacks a CXXC thioredoxin-box motif file:human/ERP29/ERP29-deep-research-falcon.md lacks the characteristic CXXC catalytic motif file:human/ERP29/ERP29-deep-research-falcon.md establishing its primary role as a chaperone rather than a catalyst |
| GO:0005783 endoplasmic reticulum | IDA PMID:9738895 ERp28, a human endoplasmic-reticulum-lumenal protein, is a m... | ACCEPT | Summary: Direct evidence (fractionation and immunofluorescence) for ER localization. Reason: IDA-supported ER localization from the founding characterization. Supporting Evidence: PMID:9738895 localizes to the endoplasmic reticulum (ER) as seen by subcellular fractionation and immunofluorescence studies |
| GO:0005788 endoplasmic reticulum lumen | NAS PMID:22064321 ERp29 induces breast cancer cell growth arrest and survival ... | ACCEPT | Summary: ER-lumen localization asserted in the literature; correct and core. Reason: ERP29 is a soluble ER-lumenal protein; consistent with its retention signal and direct localization data. Supporting Evidence: PMID:22064321 ERp29) is an ER luminal protein |
| GO:0006457 protein folding | NAS PMID:9738895 ERp28, a human endoplasmic-reticulum-lumenal protein, is a m... | KEEP AS NON CORE | Summary: ERP29 may participate in folding of secretory proteins as a non-catalytic chaperone; protein folding is a plausible downstream process. Reason: ERP29 assists folding indirectly as an escort/chaperone (it is not a foldase); protein folding is a non-core process annotation. Supporting Evidence: file:human/ERP29/ERP29-uniprot.txt possibly by participating in the folding of proteins in the ER |
| GO:0006886 intracellular protein transport | NAS PMID:9738895 ERp28, a human endoplasmic-reticulum-lumenal protein, is a m... | KEEP AS NON CORE | Summary: ERP29 participates in the trafficking/processing of secretory proteins; intracellular protein transport is a plausible downstream process. Reason: A reasonable downstream process consequence of ERP29's escort/chaperone role; non-core relative to its molecular function. Supporting Evidence: file:human/ERP29/ERP29-uniprot.txt Plays an important role in the processing of secretory proteins within the endoplasmic reticulum |
| GO:0010628 positive regulation of gene expression | IDA PMID:22064321 ERp29 induces breast cancer cell growth arrest and survival ... | KEEP AS NON CORE | Summary: In a breast-cancer overexpression model, ERP29 modulates gene expression (e.g. upregulation of p58IPK); a context-specific downstream effect. Reason: A specialized, cell-context-specific transcriptional effect from an overexpression study; not ERP29's core ER chaperone function. Supporting Evidence: PMID:22064321 upregulation of the inhibitor of the interferon-induced, double-stranded RNA-activated protein kinase, p58(IPK) |
| GO:0010629 negative regulation of gene expression | IDA PMID:22064321 ERp29 induces breast cancer cell growth arrest and survival ... | KEEP AS NON CORE | Summary: ERP29 also negatively regulates expression of certain genes in the cancer-cell model; a context-specific downstream effect. Reason: A specialized transcriptional effect in an overexpression model; non-core relative to the chaperone function. Supporting Evidence: PMID:22064321 ERp29-induced cancer cell growth arrest |
| GO:0043335 protein unfolding | NAS PMID:22064321 ERp29 induces breast cancer cell growth arrest and survival ... | KEEP AS NON CORE | Summary: ERP29 has been proposed to have a protein-unfolding activity (e.g. in toxin/virus membrane penetration); asserted in the literature but mechanistically limited. Reason: A proposed specialized activity (substrate unfolding/local conformational change) rather than ERP29's principal chaperone-binding function; retained as non-core. Supporting Evidence: file:human/ERP29/ERP29-uniprot.txt a role in protein unfolding and secretion |
| GO:0050709 negative regulation of protein secretion | IDA PMID:22064321 ERp29 induces breast cancer cell growth arrest and survival ... | KEEP AS NON CORE | Summary: ERP29 overexpression can negatively regulate secretion of specific proteins in the cancer model; a context-specific effect. Reason: A specialized, context-dependent secretion-regulation effect; non-core relative to the chaperone function. Supporting Evidence: PMID:22064321 ERp29) is an ER luminal protein that has a role in protein unfolding and secretion |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | KEEP AS NON CORE | Summary: High-throughput membrane-proteome detection; generic and uninformative for this soluble ER-lumenal protein (likely reflects ER-membrane-associated complexes or surface pool). Reason: A generic proteomic localization; uninformative relative to the precise ER-lumen localization. Supporting Evidence: file:human/ERP29/ERP29-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0009986 cell surface | IDA PMID:19995400 Platelets release novel thiol isomerase enzymes which are re... | KEEP AS NON CORE | Summary: Direct evidence that ERP29 (a thiol-isomerase-family protein) is released by platelets and recruited to the cell surface upon activation; a genuine but specialized surface pool. Reason: A real activation-dependent surface pool in platelets, but peripheral to ERP29's core ER-lumenal chaperone function. Supporting Evidence: PMID:19995400 Platelets release novel thiol isomerase enzymes which are recruited to the cell surface following activation |
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Download this section (compressed HTML)Q: What is the precise molecular contribution of ERP29 within the ER chaperone complex - does it have client specificity (e.g. thyroglobulin, connexins) distinct from its homodimerization and chaperone-binding roles?
Q: Are the cancer-associated signaling phenotypes (p38 MAPK, gene-expression and secretion control) a direct consequence of ERP29's ER chaperone function or secondary to altered ER proteostasis?
Experiment: Reconstitute ERP29 within the ER chaperone complex and test, with defined unfolded clients, whether ERP29 modulates client binding, folding kinetics or release relative to ERP29-depleted complexes.
Experiment: ERP29 knockout/knockdown in secretory cell types followed by secretome and client-folding analysis (e.g. thyroglobulin, connexin trafficking) to define its non-redundant chaperone clients.
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