ERP27 (endoplasmic reticulum resident protein 27; ER protein 27; also known as C12orf46) is a soluble, ER-lumenal, two-domain member of the protein disulfide isomerase (PDI) family that is catalytically inactive. Unlike redox-active PDIs, it lacks the CXXC thioredoxin active-site motif and therefore cannot itself catalyze thiol-disulfide exchange; its thioredoxin-like domains correspond to the non-catalytic b and b' substrate-binding domains of PDI. ERP27 binds unfolded/misfolded proteins through a hydrophobic substrate-binding cleft in its C-terminal (b'-like) domain, discriminating folded from unfolded clients, and presents/recruits the catalytic PDI-family oxidoreductase PDIA3 (ERp57) to those substrates via a defined PDIA3-binding surface (residues 230-233). It is retained in the ER lumen by a C-terminal retention motif, is induced during ER stress / the unfolded protein response, and is enriched in the pancreas. Functionally it acts as a non-catalytic chaperone/substrate-recruiter within the ER oxidative-folding machinery rather than as a disulfide isomerase.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006457 protein folding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: ERP27 assists ER protein folding as a non-catalytic substrate-binding chaperone that presents unfolded clients to PDIA3/ERp57; protein folding is a reasonable downstream process but ERP27 does not itself fold or catalyze folding. Reason: ERP27 contributes to folding only indirectly, by binding unfolded substrates and recruiting the catalytic isomerase PDIA3; it is not a foldase, so protein folding is a non-core process annotation. Supporting Evidence: file:human/ERP27/ERP27-uniprot.txt Specifically binds unfolded proteins and may recruit protein disulfide isomerase PDIA3 to unfolded substrates |
| GO:0003756 protein disulfide isomerase activity | IBA NOT GO_REF:0000033 | ACCEPT | Summary: This is a NOT (negated) annotation stating that ERP27 does NOT have protein disulfide isomerase activity. This is correct - ERP27 lacks the CXXC active-site motif and is a redox-inactive PDI-family member. Reason: The negation is well supported - ERP27 has no CXXC catalytic motif and is explicitly a catalytically redox-inactive PDI-family member; the NOT annotation correctly prevents transfer of isomerase activity. Supporting Evidence: file:human/ERP27/ERP27-uniprot.txt Does not contain a CXXC active site motif indicating that it is a catalytically redox-inactive member of the protein disulfide isomerase family. |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000044 | ACCEPT | Summary: ERP27 is a soluble ER-lumenal protein with a C-terminal ER-retention motif; this is its correct, core compartment. Reason: ER lumen is the documented localization, supported by direct experimental evidence and a retention motif. Supporting Evidence: file:human/ERP27/ERP27-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: High-throughput interactome interactions (e.g. with SGTA/O43765, EEF1D/P29692, UBQLN1/Q9UMX0). Bare protein binding is uninformative and these cytosolic partners are unrelated to ERP27's ER-lumenal substrate-presenting function. Reason: Records high-throughput physical interactions, but the generic protein binding term is uninformative; the informative ERP27 functions (misfolded protein binding, PDIA3 recruitment) are captured in core_functions. Supporting Evidence: file:human/ERP27/ERP27-uniprot.txt Q96DN0; O43765: SGTA; NbExp=7; IntAct=EBI-953772, EBI-347996; |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | KEEP AS NON CORE | Summary: Interaction-network screen (effect of genetic variants) capturing ERP27 binary interactions (SGTA, EEF1D, UBQLN1). Bare protein binding is uninformative. Reason: High-throughput binary interactions; uninformative generic term, not part of ERP27's core substrate-presenting function. Supporting Evidence: file:human/ERP27/ERP27-uniprot.txt Q96DN0; P29692: EEF1D; NbExp=5; IntAct=EBI-953772, EBI-358607; |
| 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 multiple ERP27 interactions (e.g. UBL4A/P11441, UBQLN2/Q9UHD9, BLOC1S2/Q6QNY1, MED20/Q9H944). Bare protein binding is uninformative. Reason: High-throughput binary interactions with mostly cytosolic partners; uninformative and not part of the core ER-lumenal function. Supporting Evidence: file:human/ERP27/ERP27-uniprot.txt Q96DN0; P11441: UBL4A; NbExp=3; IntAct=EBI-953772, EBI-356983; |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Neurodegeneration interactome capturing an ERP27-HTT (P42858, huntingtin) interaction. Bare protein binding is uninformative and likely an aggregation-prone-bait artifact. Reason: A single high-throughput interaction with huntingtin, unrelated to ERP27's ER substrate-presenting function; uninformative generic term. Supporting Evidence: file:human/ERP27/ERP27-uniprot.txt Q96DN0; P42858: HTT; NbExp=3; IntAct=EBI-953772, EBI-466029; |
| 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 an ERP27-EEF1D (P29692) interaction. Bare protein binding is uninformative. Reason: High-throughput AP-MS interaction; uninformative generic term, not part of the core function. Supporting Evidence: file:human/ERP27/ERP27-uniprot.txt Q96DN0; P29692: EEF1D; NbExp=5; IntAct=EBI-953772, EBI-358607; |
| GO:0005788 endoplasmic reticulum lumen | EXP PMID:16940051 ERp27, a new non-catalytic endoplasmic reticulum-located hum... | ACCEPT | Summary: Direct experimental evidence that ERP27 is located in the ER lumen. Reason: EXP-supported ER-lumen localization from the founding functional characterization. Supporting Evidence: PMID:16940051 ERp27 is a two-domain protein located in the endoplasmic reticulum |
| GO:0005515 protein binding | IPI PMID:18802093 The varicellovirus UL49.5 protein blocks the transporter ass... | KEEP AS NON CORE | Summary: Interaction captured in a study of the varicellovirus UL49.5/TAP system (partner TAP1/Q03518); a bystander affinity-capture interaction unrelated to ERP27's ER oxidative-folding function. Reason: An isolated affinity-capture interaction from an unrelated immunology study; the bare protein binding term is uninformative and not core. Supporting Evidence: file:human/ERP27/ERP27-goa.tsv UniProtKB:Q03518 |
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Download this section (compressed HTML)Q: Is ERP27 functionally dedicated to PDIA3/ERp57, or does it also hand off substrates to other PDI-family oxidoreductases, and what determines its substrate repertoire in the pancreas where it is enriched?
Q: Does loss of ERP27 measurably impair oxidative folding or secretion of specific disulfide-rich clients during ER stress, given its UPR induction?
Experiment: Co-immunoprecipitation and in vitro substrate-handoff assays measuring whether ERP27 accelerates PDIA3-catalyzed oxidative folding of a model unfolded substrate, using the PDIA3-binding-site mutants (E231/W232/D233) as negative controls.
Experiment: ERP27 knockout in pancreatic or secretory cell lines followed by ER-stress challenge and secretome/folding analysis to identify clients whose maturation depends on ERP27-mediated presentation to ERp57.
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