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.