ERP27

UniProt ID: Q96DN0
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

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.

Existing Annotations Review

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 function (unfolded-protein binding, PDIA3 recruitment) is captured separately.
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

Core Functions

Non-catalytic, ER-lumenal substrate-binding chaperone of the PDI family that specifically recognizes unfolded/misfolded proteins through a hydrophobic cleft in its b'-like domain, discriminating folded from unfolded clients.

Molecular Function:
unfolded protein binding
Cellular Locations:
endoplasmic reticulum lumen
Supporting Evidence:
  • file:human/ERP27/ERP27-uniprot.txt
    Specifically binds unfolded proteins
  • PMID:23192347
    ERp27 is able to distinguish between folded and unfolded substrates, only interacting with the latter

Recruits and presents bound unfolded substrates to the catalytic PDI-family oxidoreductase PDIA3 (ERp57) via a defined PDIA3-binding surface, acting as a substrate-recruiter within the ER oxidative-folding machinery (it does not itself catalyze disulfide isomerization).

Molecular Function:
protein-folding chaperone binding
Cellular Locations:
endoplasmic reticulum lumen
Supporting Evidence:
  • file:human/ERP27/ERP27-uniprot.txt
    may recruit protein disulfide isomerase PDIA3 to unfolded substrates
  • PMID:23192347
    present them to ERp57 for catalysis

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping
PMID:16940051
ERp27, a new non-catalytic endoplasmic reticulum-located human protein disulfide isomerase family member, interacts with ERp57.
  • ERp27 is a two-domain ER-located protein homologous to the non-catalytic b and b' domains of PDI; it binds the PDI test peptide Delta-somatostatin via its second domain, undergoes a conformational change on substrate binding, and interacts with ERp57/PDIA3 (PDIA3-binding site residues 230-233).
PMID:18802093
The varicellovirus UL49.5 protein blocks the transporter associated with antigen processing (TAP) by inhibiting essential conformational transitions in the 6+6 transmembrane TAP core complex.
PMID:23192347
The crystal structure of the protein-disulfide isomerase family member ERp27 provides insights into its substrate binding capabilities.
  • The crystal structure of redox-inactive ERp27 reveals a PDI-homologous substrate-binding cleft that adapts in size and hydrophobicity; ITC shows ERp27 distinguishes folded from unfolded substrates, only binding the latter, and is up-regulated during ER stress, presumably binding misfolded substrates and presenting them to ERp57 for catalysis.
PMID:25416956
A proteome-scale map of the human interactome network.
PMID:31515488
Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
file:human/ERP27/ERP27-uniprot.txt
UniProt entry Q96DN0 (ERP27_HUMAN), Endoplasmic reticulum resident protein 27
  • Catalytically redox-inactive (no CXXC) PDI-family member located in the ER lumen; specifically binds unfolded proteins via a C-terminal hydrophobic pocket and may recruit PDIA3 to unfolded substrates; ER-stress-induced.

Suggested Questions for Experts

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?

Suggested Experiments

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.

📚 Additional Documentation

Notes

(ERP27-notes.md)

ERP27 (C12orf46, ERp27) research notes

UniProt Q96DN0. ER-lumenal, non-catalytic PDI-family member. 273 aa, ER-retention motif (KVEL/270-273).

Core function

  • NON-CATALYTIC: lacks CXXC active-site motif -> redox-inactive PDI-family member.
  • [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."]
  • Binds unfolded proteins via a hydrophobic pocket in its C-terminal (b'-like) domain, distinguishing folded vs unfolded.
  • [file "Specifically binds unfolded proteins and may recruit protein disulfide isomerase PDIA3 to unfolded substrates"]
  • PMID:23192347
  • Recruits/presents substrates to PDIA3/ERp57 (catalytic partner). PDIA3-binding site = residues 230-233 (E231/W232/D233 critical).
  • PMID:16940051
  • Homologous to non-catalytic b and b' domains of PDI; binds Delta-somatostatin (PDI test peptide).
  • ER stress-induced. Pancreas-enriched (HPA tissue enriched pancreas).

Localization

  • ER lumen [file "SUBCELLULAR LOCATION: Endoplasmic reticulum lumen"].

Action plan

  • protein folding (GO:0006457) IBA - KEEP_AS_NON_CORE (assists folding as chaperone/substrate-presenter, not a foldase; downstream).
  • NOT|protein disulfide isomerase activity (GO:0003756) IBA negated - ACCEPT (correct, lacks CXXC).
  • ER lumen (GO:0005788) IEA + EXP - ACCEPT.
  • protein binding (many IPI) - the FUNCTIONAL one (substrate/unfolded-protein binding, PDIA3 recruitment) is core but these GOA protein binding entries are mostly HT interactome (SGTA/EEF1D/UBQLN/HTT etc), not PDIA3. KEEP_AS_NON_CORE. Note PDIA3 interaction itself is NOT in GOA protein-binding rows (those are HT partners). Core MF captured as unfolded protein binding (GO:0051082) and protein-folding chaperone binding.
  • Core MF proposals: unfolded protein binding (GO:0051082); chaperone role presenting substrates to ERp57.

Pn Notes

(ERP27-pn-notes.md)

ERP27 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q96DN0
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07b
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • Description: 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.
  • Existing/core annotation action counts: ACCEPT: 3; KEEP_AS_NON_CORE: 7

PN Consistency Summary

  • Consistency: Direct contradiction. Notes and review YAML both establish that ERP27 is a catalytically inactive, non-catalytic PDI-family member that LACKS the CXXC active-site motif and therefore cannot perform thiol-disulfide exchange. The review contains an explicit negated annotation — GO:0003756 protein disulfide isomerase activity, negated: true (IBA, GO_REF:0000033), action ACCEPT — i.e. the curated record states ERP27 does NOT have PDI activity. The PN group node projects the exact same term GO:0003756 as new_to_goa (a positive addition). PN proposes adding the precise term the review explicitly negates. This is the hardest conflict in the batch.
  • PN story / NEW pressure: GO:0003756 (OLS-verified) must NOT be added to ERP27 — it is biologically wrong (no CXXC) and is already correctly captured as a NOT annotation in GOA/review. ERP27's real core functions are GO:0051082 unfolded protein binding (substrate discrimination via the b'-like cleft, PMID:23192347) and GO:0051087 protein-folding chaperone binding (recruits/presents substrates to the catalytic PDIA3/ERp57, PMID:16940051/23192347) — both added in the review, neither surfaced by the PN node. Conclusion: PN projection over-reaches / is incorrect; the review's substrate-presenter framing is the right model.
  • Evidence alignment: PN dossier lists no reference titles. Review evidence (PMID:16940051 founding non-catalytic characterization, GOA-anchored to GO:0005788 EXP; PMID:23192347 crystal structure + ITC substrate discrimination) is reviewer-supplied and directly supports the non-catalytic substrate-presenter role. No shared citation list to compare; the biology flatly opposes the PN GO:0003756 projection.
  • Verdict: Contradiction — PN projects GO:0003756 (new_to_goa) onto a gene whose review explicitly NEGATES that exact term (no CXXC, catalytically inactive). PN over-reaches; review is correct. Recommended edits: [MAP] remove/suppress the GO:0003756 projection for ERP27 (it is a non-catalytic PDI-family member; the term is correctly a NOT annotation). If a positive mapping is wanted, target GO:0051082 unfolded protein binding and/or GO:0051087 protein-folding chaperone binding (both OLS-real, both already in the review's core_functions).

Full Consistency Review

  • UniProt: Q96DN0 · batch: proteostasis-batch-2026-06-07b · review status: COMPLETE
  • PN placement: ER proteostasis|Folding enzyme|Protein disulfide isomerases. PN-node mapping: group Protein disulfide isomerases=mapped→GO:0003756 protein disulfide isomerase activity (new_to_goa); class Folding enzyme=no_mapping; branch=no_mapping.
  • Consistency: Direct contradiction. Notes and review YAML both establish that ERP27 is a catalytically inactive, non-catalytic PDI-family member that LACKS the CXXC active-site motif and therefore cannot perform thiol-disulfide exchange. The review contains an explicit negated annotation — GO:0003756 protein disulfide isomerase activity, negated: true (IBA, GO_REF:0000033), action ACCEPT — i.e. the curated record states ERP27 does NOT have PDI activity. The PN group node projects the exact same term GO:0003756 as new_to_goa (a positive addition). PN proposes adding the precise term the review explicitly negates. This is the hardest conflict in the batch.
  • PN story / NEW pressure: GO:0003756 (OLS-verified) must NOT be added to ERP27 — it is biologically wrong (no CXXC) and is already correctly captured as a NOT annotation in GOA/review. ERP27's real core functions are GO:0051082 unfolded protein binding (substrate discrimination via the b'-like cleft, PMID:23192347) and GO:0051087 protein-folding chaperone binding (recruits/presents substrates to the catalytic PDIA3/ERp57, PMID:16940051/23192347) — both added in the review, neither surfaced by the PN node. Conclusion: PN projection over-reaches / is incorrect; the review's substrate-presenter framing is the right model.
  • Mapping strategy: This gene exposes the core flaw of the Protein disulfide isomerases group projecting GO:0003756 to all leaves: the node lumps catalytic isomerases (P4HB, AGR2-debated), redox oxidases (ERO1A/B), and non-catalytic members (ERP27). For ERP27 the projection is not merely broad (TOMM20/HSPA8/RAB7A precedent) but actively wrong, contradicting an explicit negation. Gene-level mapping for ERP27 should be no_mapping for GO:0003756 (or carry the negation), with any positive mapping pointing at unfolded protein binding / chaperone-binding.
  • Evidence alignment: PN dossier lists no reference titles. Review evidence (PMID:16940051 founding non-catalytic characterization, GOA-anchored to GO:0005788 EXP; PMID:23192347 crystal structure + ITC substrate discrimination) is reviewer-supplied and directly supports the non-catalytic substrate-presenter role. No shared citation list to compare; the biology flatly opposes the PN GO:0003756 projection.
  • Verdict: Contradiction — PN projects GO:0003756 (new_to_goa) onto a gene whose review explicitly NEGATES that exact term (no CXXC, catalytically inactive). PN over-reaches; review is correct. Recommended edits: [MAP] remove/suppress the GO:0003756 projection for ERP27 (it is a non-catalytic PDI-family member; the term is correctly a NOT annotation). If a positive mapping is wanted, target GO:0051082 unfolded protein binding and/or GO:0051087 protein-folding chaperone binding (both OLS-real, both already in the review's core_functions).

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07b
  • review_yaml: genes/human/ERP27/ERP27-ai-review.yaml
  • PN workbook rows: 1

PN row 1: ER proteostasis | Folding enzyme | Protein disulfide isomerases

  • UniProt: Q96DN0
  • In branches: ER
  • PN-node mapping records (path + ancestors):
    • [group] ER proteostasis|Folding enzyme|Protein disulfide isomerases
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0003756 protein disulfide isomerase activity]
      rationale: This PN group captures the canonical ER protein-disulfide-isomerase folding enzymes. GO protein disulfide isomerase activity is the cleanest propagation target for the catalytically active family members.
    • [class] ER proteostasis|Folding enzyme
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
    • [branch] ER proteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (1)

  • GO:0003756 protein disulfide isomerase activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Folding enzyme|Protein disulfide isomerases

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
id: Q96DN0
gene_symbol: ERP27
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
existing_annotations:
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/ERP27/ERP27-uniprot.txt
      supporting_text: Specifically binds unfolded proteins and may recruit protein disulfide isomerase PDIA3 to unfolded substrates
- term:
    id: GO:0003756
    label: protein disulfide isomerase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  negated: true
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/ERP27/ERP27-uniprot.txt
      supporting_text: Does not contain a CXXC active site motif indicating that it is a catalytically redox-inactive member of the protein disulfide isomerase family.
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ERP27 is a soluble ER-lumenal protein with a C-terminal ER-retention motif; this is its correct, core compartment.
    action: ACCEPT
    reason: ER lumen is the documented localization, supported by direct experimental evidence and a retention motif.
    supported_by:
    - reference_id: file:human/ERP27/ERP27-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Records high-throughput physical interactions, but the generic protein binding term is uninformative; the informative ERP27 function (unfolded-protein binding, PDIA3 recruitment) is captured separately.
    supported_by:
    - reference_id: file:human/ERP27/ERP27-uniprot.txt
      supporting_text: 'Q96DN0; O43765: SGTA; NbExp=7; IntAct=EBI-953772, EBI-347996;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: Interaction-network screen (effect of genetic variants) capturing ERP27 binary interactions (SGTA, EEF1D, UBQLN1). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput binary interactions; uninformative generic term, not part of ERP27's core substrate-presenting function.
    supported_by:
    - reference_id: file:human/ERP27/ERP27-uniprot.txt
      supporting_text: 'Q96DN0; P29692: EEF1D; NbExp=5; IntAct=EBI-953772, EBI-358607;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Reference binary interactome capturing multiple ERP27 interactions (e.g. UBL4A/P11441, UBQLN2/Q9UHD9, BLOC1S2/Q6QNY1, MED20/Q9H944). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput binary interactions with mostly cytosolic partners; uninformative and not part of the core ER-lumenal function.
    supported_by:
    - reference_id: file:human/ERP27/ERP27-uniprot.txt
      supporting_text: 'Q96DN0; P11441: UBL4A; NbExp=3; IntAct=EBI-953772, EBI-356983;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Neurodegeneration interactome capturing an ERP27-HTT (P42858, huntingtin) interaction. Bare protein binding is uninformative and likely an aggregation-prone-bait artifact.
    action: KEEP_AS_NON_CORE
    reason: A single high-throughput interaction with huntingtin, unrelated to ERP27's ER substrate-presenting function; uninformative generic term.
    supported_by:
    - reference_id: file:human/ERP27/ERP27-uniprot.txt
      supporting_text: 'Q96DN0; P42858: HTT; NbExp=3; IntAct=EBI-953772, EBI-466029;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-purification interactome capturing an ERP27-EEF1D (P29692) interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput AP-MS interaction; uninformative generic term, not part of the core function.
    supported_by:
    - reference_id: file:human/ERP27/ERP27-uniprot.txt
      supporting_text: 'Q96DN0; P29692: EEF1D; NbExp=5; IntAct=EBI-953772, EBI-358607;'
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: EXP
  original_reference_id: PMID:16940051
  qualifier: located_in
  review:
    summary: Direct experimental evidence that ERP27 is located in the ER lumen.
    action: ACCEPT
    reason: EXP-supported ER-lumen localization from the founding functional characterization.
    supported_by:
    - reference_id: PMID:16940051
      supporting_text: ERp27 is a two-domain protein located in the endoplasmic reticulum
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18802093
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: An isolated affinity-capture interaction from an unrelated immunology study; the bare protein binding term is uninformative and not core.
    supported_by:
    - reference_id: file:human/ERP27/ERP27-goa.tsv
      supporting_text: UniProtKB:Q03518
core_functions:
- description: Non-catalytic, ER-lumenal substrate-binding chaperone of the PDI family that specifically recognizes unfolded/misfolded proteins through a hydrophobic cleft in its b'-like domain, discriminating folded from unfolded clients.
  molecular_function:
    id: GO:0051082
    label: unfolded protein binding
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  supported_by:
  - reference_id: file:human/ERP27/ERP27-uniprot.txt
    supporting_text: Specifically binds unfolded proteins
  - reference_id: PMID:23192347
    supporting_text: ERp27 is able to distinguish between folded and unfolded substrates, only interacting with the latter
- description: Recruits and presents bound unfolded substrates to the catalytic PDI-family oxidoreductase PDIA3 (ERp57) via a defined PDIA3-binding surface, acting as a substrate-recruiter within the ER oxidative-folding machinery (it does not itself catalyze disulfide isomerization).
  molecular_function:
    id: GO:0051087
    label: protein-folding chaperone binding
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  supported_by:
  - reference_id: file:human/ERP27/ERP27-uniprot.txt
    supporting_text: may recruit protein disulfide isomerase PDIA3 to unfolded substrates
  - reference_id: PMID:23192347
    supporting_text: present them to ERp57 for catalysis
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping
  findings: []
- id: PMID:16940051
  title: ERp27, a new non-catalytic endoplasmic reticulum-located human protein disulfide isomerase family member, interacts with ERp57.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_16940051.md title matches YAML; original identification of ERp27 as a non-catalytic ER PDI-family member that binds peptide substrate and interacts with ERp57. GOA anchors this PMID to GO:0005788 (ER lumen, EXP)."
  findings:
  - statement: ERp27 is a two-domain ER-located protein homologous to the non-catalytic b and b' domains of PDI; it binds the PDI test peptide Delta-somatostatin via its second domain, undergoes a conformational change on substrate binding, and interacts with ERp57/PDIA3 (PDIA3-binding site residues 230-233).
    reference_section_type: ABSTRACT
- id: PMID:18802093
  title: The varicellovirus UL49.5 protein blocks the transporter associated with antigen processing (TAP) by inhibiting essential conformational transitions in the 6+6 transmembrane TAP core complex.
  findings: []
- id: PMID:23192347
  title: The crystal structure of the protein-disulfide isomerase family member ERp27 provides insights into its substrate binding capabilities.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_23192347.md title matches YAML; crystal structure plus ITC establish the core MF — ERp27 distinguishes folded vs unfolded substrates and presents them to ERp57 (unfolded protein binding / chaperone-binding adapter)."
  findings:
  - statement: The crystal structure of redox-inactive ERp27 reveals a PDI-homologous substrate-binding cleft that adapts in size and hydrophobicity; ITC shows ERp27 distinguishes folded from unfolded substrates, only binding the latter, and is up-regulated during ER stress, presumably binding misfolded substrates and presenting them to ERp57 for catalysis.
    reference_section_type: ABSTRACT
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: file:human/ERP27/ERP27-uniprot.txt
  title: UniProt entry Q96DN0 (ERP27_HUMAN), Endoplasmic reticulum resident protein 27
  findings:
  - statement: Catalytically redox-inactive (no CXXC) PDI-family member located in the ER lumen; specifically binds unfolded proteins via a C-terminal hydrophobic pocket and may recruit PDIA3 to unfolded substrates; ER-stress-induced.
    reference_section_type: OTHER
proposed_new_terms: []
suggested_questions:
- question: 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?
- question: Does loss of ERP27 measurably impair oxidative folding or secretion of specific disulfide-rich clients during ER stress, given its UPR induction?
suggested_experiments:
- description: 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.
- description: 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.