id: P06761
gene_symbol: Hspa5
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:10116
  label: Rattus norvegicus
description: >-
  Hspa5 (BiP/GRP78) is the ER-resident member of the HSP70 chaperone family. It
  functions as an ATP-dependent protein folding chaperone in the ER lumen, assisting
  in de novo folding of nascent polypeptides entering the secretory pathway and in
  quality control of misfolded proteins. BiP is a key regulator of the unfolded
  protein response (UPR), acting as a repressor of both IRE1 and PERK signaling
  arms by binding their luminal domains in the unstressed state and releasing them
  upon accumulation of misfolded proteins. It also participates in ERAD, post-
  translational translocation, and ER protein retention. BiP forms part of large
  ER chaperone complexes with co-chaperones (e.g., ERdj4, ERdj5), GRP94, and
  protein disulfide isomerases. It is also found at the cell surface in some
  contexts where it can act as a receptor for extracellular ligands.
existing_annotations:
# ========== IBA annotations (phylogenetic) ==========
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for nuclear localization. BiP is primarily an ER lumen protein,
      but some HSP70 family members are found in the nucleus. UniProt notes cytoplasm
      and ER lumen as primary locations (PMID:3087629). Nuclear localization is not
      well documented for BiP/GRP78 specifically in the rat, though the IBA may
      reflect ancestral HSP70 family properties shared with cytoplasmic/nuclear
      paralogs.
    action: KEEP_AS_NON_CORE
    reason: >-
      Nuclear localization is not a core feature of BiP/GRP78. The IBA likely
      reflects shared HSP70 family properties. BiP has a signal peptide and KDEL
      retention signal directing it to the ER lumen. Nucleus is not a primary
      location for this protein, though minor amounts may be detected.

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for cytoplasmic localization. UniProt lists cytoplasm as a
      subcellular location for BiP, likely reflecting release from ER under stress
      or during apoptosis. This is a secondary localization for this ER-resident
      protein.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytoplasmic localization is secondary to BiP's primary ER lumen residency.
      The IBA reflects broad HSP70 family cytoplasmic presence. BiP can be released
      from ER under certain conditions, but the cytoplasm is not its primary
      functional location.

- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for ATP hydrolysis activity. BiP has a well-characterized
      nucleotide-binding domain (NBD) and is classified as EC 3.6.4.10 in UniProt.
      The ATPase activity is central to its chaperone cycle, regulated by J-domain
      co-chaperones such as ERdj4 and ERdj5.
    action: ACCEPT
    reason: >-
      ATP hydrolysis is a core molecular function of BiP/GRP78. UniProt assigns
      EC 3.6.4.10 and notes "ATP + H2O = ADP + phosphate + H(+)" as the catalytic
      reaction. The ATPase activity drives the allosteric coupling between the
      nucleotide-binding and substrate-binding domains that is essential for
      chaperone function.
    supported_by:
      - reference_id: GO_REF:0000033
        supporting_text: "IBA from phylogenetic inference across HSP70 family members with demonstrated ATPase activity"

- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for heat shock protein binding. BiP interacts with multiple
      other chaperones in the ER, including GRP94 (HSP90B1), and with J-domain
      co-chaperones (DNAJB9/ERdj4, DNAJC10/ERdj5). UniProt documents extensive
      interactions with other chaperones and co-chaperones.
    action: ACCEPT
    reason: >-
      BiP physically interacts with multiple heat shock protein family members,
      including GRP94 and various J-domain proteins. This is well-supported by
      UniProt interaction data and the known ER chaperone complex composition
      (PMID:12475965). The IBA is phylogenetically sound for HSP70 family.
    supported_by:
      - reference_id: PMID:22665516
        supporting_text: "Chaperones and foldases in the endoplasmic reticulum (ER) ensure correct protein folding. [...] we have mapped interactions between ER-lumenal chaperones and foldases and describe their organization in multiprotein complexes."

- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for protein folding chaperone activity. This is the core
      molecular function of BiP/GRP78 as an HSP70 family foldase in the ER. Per
      the UPB project decision rules, HSP70 family members are classified as
      context-dependent foldase/holdase, with GO:0044183 as the primary MF term.
    action: ACCEPT
    reason: >-
      Protein folding chaperone is the core molecular function of BiP. UniProt
      states BiP "plays a key role in protein folding and quality control in the
      endoplasmic reticulum lumen." The IBA correctly assigns this term at the
      right level of specificity for an HSP70 family member. Per UPB project
      rules for HSP70: MODIFY GO:0051082 to GO:0044183, which this IBA already
      captures.

- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for involvement in the ERAD pathway. BiP participates in ERAD
      through its interaction with DNAJC10/ERdj5 to facilitate release of substrates
      from the chaperone system for degradation, and through complexes with ERAD
      components such as ERLEC1, OS9, SEL1L, and SYVN1 (UniProt).
    action: ACCEPT
    reason: >-
      BiP plays a well-documented role in ERAD. UniProt states it is "Involved in
      the correct folding of proteins and degradation of misfolded proteins via its
      interaction with DNAJC10/ERdj5." PMID:23444373 demonstrates BiP interaction
      with ERAD machinery via SDF2L1 in the context of misfolded proinsulin
      degradation.
    supported_by:
      - reference_id: PMID:23444373
        supporting_text: "SDF2L1 interacts with the ER chaperone GRP78/BiP, the ER-associated degradation (ERAD) machinery and with misfolded proinsulin."

- term:
    id: GO:0016020
    label: membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for membrane localization. BiP is found associated with ER
      membranes (where it interacts with the translocon SEC61 complex) and can also
      be found at the cell surface. This is a very broad localization term.
    action: ACCEPT
    reason: >-
      While very broad, this term is accurate. BiP associates with ER membranes
      during translocation (interacting with SEC61 and SEC62) and is also found at
      the cell surface. The IBA is acceptable as a parent term that is subsumed by
      more specific membrane localizations.

- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for protein refolding. BiP, as an HSP70 family foldase, can
      participate in refolding of misfolded proteins in the ER. This is consistent
      with its role in ER quality control.
    action: ACCEPT
    reason: >-
      Protein refolding is a documented function of HSP70 chaperones including BiP.
      In the ER quality control context, BiP can assist in attempts to refold
      misfolded proteins before they are targeted for ERAD. The IBA is
      phylogenetically consistent across HSP70 family.

- term:
    id: GO:0034663
    label: endoplasmic reticulum chaperone complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for ER chaperone complex membership. BiP is a well-documented
      component of ER chaperone complexes. PMID:12475965 directly demonstrates BiP
      is part of a large chaperone multiprotein complex with DNAJB11, HSP90B1,
      HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1, and ERP29.
    action: ACCEPT
    reason: >-
      BiP is a core component of the ER chaperone complex. UniProt documents its
      membership in multiprotein complexes (PubMed:12475965). This is a fundamental
      aspect of BiP function.
    supported_by:
      - reference_id: PMID:22665516
        supporting_text: "we have mapped interactions between ER-lumenal chaperones and foldases and describe their organization in multiprotein complexes"

- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for ER lumen localization. This is the primary subcellular
      location of BiP/GRP78. The protein has an N-terminal signal peptide (aa 1-18)
      and a C-terminal KDEL ER retention motif (aa 651-654).
    action: ACCEPT
    reason: >-
      The ER lumen is the primary and best-characterized subcellular location for
      BiP/GRP78. UniProt lists "Endoplasmic reticulum lumen" as the primary
      subcellular location. The signal peptide and KDEL retention signal are
      documented in the UniProt feature table.

- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for involvement in the ER unfolded protein response. BiP is
      a master regulator of the UPR, acting as a repressor of both IRE1 and PERK
      signaling pathways by binding their luminal domains in the unstressed state.
    action: ACCEPT
    reason: >-
      Involvement in the ER UPR is a core function of BiP. UniProt states BiP
      "Acts as a key repressor of the EIF2AK3/PERK and ERN1/IRE1-mediated unfolded
      protein response (UPR)." This is one of the most well-established biological
      processes for BiP.

# ========== IEA annotations (electronic) ==========
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA from UniProt keyword mapping. BiP binds ATP via its nucleotide-binding
      domain (NBD). This is a very broad term; more specific terms (ATP binding,
      ATP hydrolysis activity) are also annotated.
    action: ACCEPT
    reason: >-
      Nucleotide binding is accurate but very broad. It is subsumed by the more
      specific ATP binding (GO:0005524) annotation. Acceptable as an IEA that
      does not conflict with more specific annotations.

- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA from InterPro/UniProt keyword mapping. BiP has a well-characterized
      ATP-binding domain. Multiple ATP-binding residues are documented in UniProt
      feature annotations.
    action: ACCEPT
    reason: >-
      ATP binding is well established for BiP. UniProt documents multiple ATP
      binding sites (residues 36-39, 96, 227-229, 293-300, 364-367). This is
      fundamental to the chaperone cycle.

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA from UniProt subcellular location mapping. Duplicate of the IBA
      annotation for cytoplasm. UniProt lists cytoplasm as a subcellular location.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytoplasmic localization is secondary to ER lumen. Acceptable as a
      broader IEA that is consistent with the IBA annotation.

- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA from UniProt subcellular location mapping for ER lumen. Duplicates
      the IBA annotation. ER lumen is the primary location of BiP.
    action: ACCEPT
    reason: >-
      ER lumen is the primary location. This IEA is consistent with the IBA
      and with the signal peptide and KDEL retention signals documented in
      UniProt.

- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA from UniProt subcellular location. UniProt notes BiP localizes to the
      cell surface in epithelial cells, with high levels of free iron promoting
      cell surface localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cell surface localization is a secondary, non-canonical location for BiP
      observed in specific contexts (epithelial cells, stress, cancer cells).
      It is not the primary functional location but is documented in UniProt.

- term:
    id: GO:0016787
    label: hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA from UniProt keyword mapping. BiP has ATPase (hydrolase) activity
      (EC 3.6.4.10). This is a very broad parent term of the more informative
      ATP hydrolysis activity.
    action: ACCEPT
    reason: >-
      Hydrolase activity is accurate but very broad. It is the parent of ATP
      hydrolysis activity (GO:0016887) which is also annotated. Acceptable as
      a general IEA.

- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA from InterPro/RHEA mapping for ATP hydrolysis activity. Duplicates
      the IBA annotation. BiP is classified as EC 3.6.4.10.
    action: ACCEPT
    reason: >-
      ATP hydrolysis activity is a core function of BiP, consistent with the
      IBA annotation and the EC classification.

- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA from ARBA machine learning. BiP is a central player in the ER stress
      response, both as a sensor (titrated away from IRE1/PERK by misfolded
      proteins) and as a chaperone that helps resolve the stress.
    action: ACCEPT
    reason: >-
      Response to ER stress is a core biological process for BiP. It is both
      induced by ER stress (at the transcriptional level, as GRP78 is a glucose-
      regulated protein) and functionally involved in resolving it.

- term:
    id: GO:0042470
    label: melanosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA from UniProt subcellular location. UniProt notes BiP was "Identified by
      mass spectrometry in melanosome fractions from stage I to stage IV" based on
      similarity to human HSPA5.
    action: KEEP_AS_NON_CORE
    reason: >-
      Melanosome localization is based on proteomic detection by mass spectrometry
      and transferred by similarity. BiP is an abundant ER protein and melanosomes
      originate from the secretory pathway, so its presence may reflect transit
      rather than functional localization. Not a core compartment.

- term:
    id: GO:0051787
    label: misfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA from ARBA for misfolded protein binding. BiP binds misfolded proteins
      in the ER as part of its quality control function. This is consistent with
      its roles in ERAD and UPR.
    action: ACCEPT
    reason: >-
      Misfolded protein binding is a well-established function of BiP. It binds
      hydrophobic patches exposed on misfolded proteins to prevent aggregation
      and either promote refolding or target substrates for ERAD.

# ========== IPI annotations (protein interaction) ==========
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17981125
  review:
    summary: >-
      IPI for protein binding based on interaction with Sigma-1 receptor (Sigmar1).
      PMID:17981125 shows Sig-1Rs form a complex with BiP at the MAM (mitochondrion-
      associated ER membrane). Upon ER Ca2+ depletion, Sig-1Rs dissociate from BiP.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. The actual interaction is with Sigma-1
      receptor at the MAM, regulating Ca2+ signaling. A more specific binding term
      or a BP annotation capturing BiP's role in MAM-mediated signaling would be
      more informative.
    supported_by:
      - reference_id: PMID:17981125
        supporting_text: "Normally, Sig-1Rs form a complex at MAM with another chaperone, BiP. Upon ER Ca(2+) depletion or via ligand stimulation, Sig-1Rs dissociate from BiP, leading to a prolonged Ca(2+) signaling into mitochondria via IP3Rs."

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7916014
  review:
    summary: >-
      IPI for protein binding based on interaction with thyroglobulin (Tg).
      PMID:7916014 demonstrates that BiP associates with thyroglobulin during
      maturation in thyroid cells, acting as a molecular chaperone.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. The interaction with thyroglobulin
      represents BiP's chaperone function (binding client proteins during folding).
      This is better captured by GO:0044183 (protein folding chaperone) which is
      already annotated.
    supported_by:
      - reference_id: PMID:7916014
        supporting_text: "BiP could be coimmunoprecipitated with anti-Tg antibodies in the absence of cross-linking [...] Coprecipitation of BiP and Tg was abolished when ATP and Mg2+ were added to cell lysates."

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18757373
  review:
    summary: >-
      IPI for protein binding based on interaction with DMP1 (dentin matrix
      protein 1). PMID:18757373 shows GRP78 mediates endocytosis of DMP1 at the
      cell surface. This represents BiP's cell-surface receptor function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. This study demonstrates BiP acting as
      a cell surface receptor for DMP1 endocytosis, a non-canonical function
      distinct from its ER chaperone role. A more specific term would be needed
      to capture this receptor function.
    supported_by:
      - reference_id: PMID:18757373
        supporting_text: "cellular uptake of DMP1 occurs through endocytosis. Interestingly, this process is initiated by DMP1 binding to the glucose-regulated protein-78 (GRP-78) localized on the plasma membrane of preodontoblast cells."

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9714535
  review:
    summary: >-
      IPI for protein binding based on interaction with ERp29 (P52555).
      PMID:9714535 shows ERp29 interacts with BiP/GRP78 in the ER. ERp29 is
      another ER-resident protein involved in protein folding/secretion.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. The interaction with ERp29 likely
      reflects ER chaperone complex formation. The ER chaperone complex
      annotation (GO:0034663) already captures this aspect. More specific
      binding terms would be preferable.
    supported_by:
      - reference_id: PMID:9714535
        supporting_text: "ERp29 interacts with a number of ER proteins, one of which was previously identified as BiP/GRP78."

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12514190
  review:
    summary: >-
      IPI for protein binding based on interaction with TMEM132A (GBP, GRP78-
      binding protein). PMID:12514190 identified TMEM132A as a novel GRP78-
      binding protein in the rat brain using GST pull-down assay.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. The interaction with TMEM132A may
      relate to BiP's role in neuronal cell survival during development, but
      a more specific binding term is needed. The study used GST pull-down
      which demonstrates physical interaction but protein binding is too vague.
    supported_by:
      - reference_id: PMID:12514190
        supporting_text: "we performed a GST-tagged GBP pull-down assay in PC12 lysates and identified GRP78, one of the heat shock proteins, as a counterpart."

# ========== ISO/ISS annotations (sequence/ortholog-based) ==========
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from RGD based on human HSPA5 (P11021). ER lumen is the primary
      subcellular location for BiP. Consistent with IBA and IEA annotations.
    action: ACCEPT
    reason: >-
      ER lumen is the primary location for BiP. This ISO is redundant with
      the IBA and IEA annotations but correctly reflects the primary
      subcellular location.

- term:
    id: GO:0140311
    label: protein sequestering activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5 for protein sequestering activity. This likely relates
      to BiP's ability to sequester/bind IRE1 and PERK luminal domains, preventing
      their activation in the unstressed ER. BiP also oligomerizes to sequester
      itself when not needed.
    action: ACCEPT
    reason: >-
      Protein sequestering activity accurately captures BiP's function of binding
      and sequestering UPR sensor proteins (IRE1, PERK) to keep them inactive.
      UniProt describes BiP binding and inactivating both PERK and IRE1 in
      unstressed conditions, and BiP self-oligomerization as a storage mechanism.

- term:
    id: GO:1903894
    label: regulation of IRE1-mediated unfolded protein response
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5 for regulation of IRE1-mediated UPR. BiP binds the
      luminal domain of IRE1 (recruited by DNAJB9/ERdj4), preventing dimerization
      and activation. Upon misfolded protein accumulation, BiP releases from IRE1.
    action: ACCEPT
    reason: >-
      Regulation of IRE1-mediated UPR is a core function of BiP. UniProt states
      BiP is "recruited by DNAJB9/ERdj4 to the luminal region of ERN1/IRE1,
      leading to disrupt the dimerization of ERN1/IRE1, thereby inactivating
      ERN1/IRE1."

- term:
    id: GO:0030291
    label: protein serine/threonine kinase inhibitor activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5 for protein Ser/Thr kinase inhibitor activity. This
      refers to BiP's ability to bind and inhibit PERK (EIF2AK3), a Ser/Thr
      kinase that phosphorylates eIF2alpha during the UPR.
    action: ACCEPT
    reason: >-
      BiP directly binds and inhibits PERK, a serine/threonine kinase. UniProt
      states BiP "binds and inactivates EIF2AK3/PERK in unstressed cells."
      This is a specific, well-characterized molecular function.

- term:
    id: GO:1903898
    label: negative regulation of PERK-mediated unfolded protein response
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5. BiP binds PERK luminal domain, preventing its
      homodimerization and activation. Release of BiP from PERK allows PERK
      activation during ER stress.
    action: ACCEPT
    reason: >-
      Negative regulation of PERK-mediated UPR is a core function of BiP.
      UniProt states BiP binds and inactivates PERK, and "Accumulation of
      misfolded protein in the endoplasmic reticulum causes release of HSPA5/BiP
      from [...] EIF2AK3/PERK, allowing their homodimerization and subsequent
      activation."

- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from mouse Hspa5 (MGI:95835) for protein folding chaperone activity.
      Redundant with the IBA annotation. This is the core molecular function.
    action: ACCEPT
    reason: >-
      Protein folding chaperone is the core MF for BiP. This ISO is consistent
      with the IBA and with UniProt functional description.

- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS based on C. elegans BiP ortholog (G3I8R9) for ATP hydrolysis activity.
      Redundant with IBA and IEA annotations. Core enzymatic function.
    action: ACCEPT
    reason: >-
      ATP hydrolysis is a core function. This ISS is consistent with other
      evidence codes for the same term.

- term:
    id: GO:0031333
    label: negative regulation of protein-containing complex assembly
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS based on C. elegans BiP. This likely refers to BiP's ability to prevent
      premature assembly or aggregation of protein complexes through its chaperone
      activity, or its role in preventing IRE1/PERK dimerization.
    action: KEEP_AS_NON_CORE
    reason: >-
      While BiP does prevent IRE1 and PERK dimerization (a form of negative
      regulation of complex assembly), this is a broad term. The more specific
      terms for IRE1 and PERK regulation are also annotated. This annotation
      could also reflect prevention of protein aggregation. Acceptable but not
      core.

- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5 for ATP binding. Redundant with IEA annotation.
      Core function with well-documented binding sites in UniProt.
    action: ACCEPT
    reason: >-
      ATP binding is fundamental to BiP's chaperone cycle. UniProt documents
      multiple ATP binding sites. Consistent with other evidence codes.

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5 for cytoplasm. Redundant with IBA and IEA annotations.
      Secondary localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytoplasm is a secondary localization for BiP. Consistent with other
      evidence codes.

- term:
    id: GO:0031204
    label: post-translational protein targeting to membrane, translocation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS based on human HSPA5 for post-translational translocation. UniProt
      states BiP "Plays an auxiliary role in post-translational transport of
      small presecretory proteins across endoplasmic reticulum (ER)."
    action: ACCEPT
    reason: >-
      BiP has a documented role in post-translational translocation of small
      presecretory proteins across the ER membrane, functioning as an allosteric
      modulator of the SEC61 translocon and cooperating with SEC62.

- term:
    id: GO:0031204
    label: post-translational protein targeting to membrane, translocation
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5. Duplicate of the ISS annotation for the same
      process. Same rationale applies.
    action: ACCEPT
    reason: >-
      Post-translational translocation is a documented function of BiP.
      This ISO is redundant with the ISS but uses different reference basis.

- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5 for mitochondrial localization. BiP is found at the
      MAM (mitochondrion-associated ER membrane) where it interacts with Sigma-1
      receptor (PMID:17981125). This is technically ER membrane apposed to
      mitochondria rather than true mitochondrial localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      BiP's association with mitochondria is indirect, via the MAM contact sites.
      PMID:17981125 shows BiP complexes with Sigma-1 receptor at the MAM. This
      is more accurately described as ER membrane localization at MAM contact
      sites rather than mitochondrial localization per se.
    supported_by:
      - reference_id: PMID:17981125
        supporting_text: "Sig-1Rs form a complex at MAM with another chaperone, BiP."

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS based on human HSPA5 for cytosol localization. BiP may be released
      from ER to cytosol under stress conditions or during apoptosis.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosolic localization is not a primary location for BiP. It may occur
      under stress or pathological conditions. Not a core compartment.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5 for cytosol. Redundant with ISS annotation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol is not a primary location for BiP. Redundant with ISS annotation.

- term:
    id: GO:0036498
    label: IRE1-mediated unfolded protein response
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from mouse Hspa5 for IRE1-mediated UPR. BiP is a central regulator
      of IRE1 signaling by binding its luminal domain.
    action: ACCEPT
    reason: >-
      BiP's involvement in the IRE1 pathway is well established. This is
      related to but more specific than the general ER UPR annotation.

- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from mouse Hspa5 for ER UPR. Redundant with IBA annotation. Core
      biological process for BiP.
    action: ACCEPT
    reason: >-
      ER UPR is a core process for BiP. Consistent with IBA and other
      annotations.

- term:
    id: GO:1903895
    label: negative regulation of IRE1-mediated unfolded protein response
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS based on C. elegans BiP for negative regulation of IRE1-mediated UPR.
      BiP binds IRE1 luminal domain (recruited by ERdj4), preventing its
      dimerization and activation.
    action: ACCEPT
    reason: >-
      Negative regulation of IRE1-mediated UPR is a well-established function
      of BiP. UniProt states BiP disrupts IRE1 dimerization by binding its
      luminal region.

- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5 for protein-containing complex. Very broad
      localization term. BiP forms multiple complexes in the ER.
    action: KEEP_AS_NON_CORE
    reason: >-
      While accurate (BiP forms many complexes), this term is very broad and
      uninformative. The more specific ER chaperone complex annotation
      (GO:0034663) is more appropriate.

- term:
    id: GO:0034663
    label: endoplasmic reticulum chaperone complex
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from mouse and human HSPA5. Redundant with IBA annotation for ER
      chaperone complex. Core complex membership.
    action: ACCEPT
    reason: >-
      ER chaperone complex is a well-documented localization. Consistent
      with IBA annotation.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from mouse Hspa5 for plasma membrane localization. BiP has been
      found at the cell surface/plasma membrane in various contexts, where it
      can serve as a receptor for extracellular ligands.
    action: KEEP_AS_NON_CORE
    reason: >-
      Plasma membrane localization is a non-canonical, secondary location
      for BiP, observed particularly in cancer cells and in specific
      physiological contexts. UniProt notes "Localizes to the cell surface
      in epithelial cells."

- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from mouse and human HSPA5 for ER membrane localization. BiP
      associates with ER membranes through its interaction with the SEC61
      translocon complex.
    action: ACCEPT
    reason: >-
      ER membrane association is consistent with BiP's role in post-
      translational translocation via the SEC61 channel and its interaction
      with transmembrane co-chaperones.

- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5 for enzyme binding. BiP interacts with various
      enzymes in the ER including protein disulfide isomerases and the
      serine/threonine kinase PERK.
    action: KEEP_AS_NON_CORE
    reason: >-
      Enzyme binding is a broad term. BiP does interact with enzymes (PDIs,
      PERK, IRE1), but more specific terms capture these interactions better.
      The protein Ser/Thr kinase inhibitor activity annotation already covers
      the PERK interaction.

- term:
    id: GO:0030335
    label: positive regulation of cell migration
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS based on human HSPA5 for positive regulation of cell migration.
      UniProt notes interaction with CEMIP that "induces calcium leakage from
      the endoplasmic reticulum and cell migration."
    action: KEEP_AS_NON_CORE
    reason: >-
      Positive regulation of cell migration is a downstream effect of BiP's
      interaction with CEMIP rather than a direct function. This is a
      secondary, pleiotropic effect and not a core function of the ER chaperone.

- term:
    id: GO:0035437
    label: maintenance of protein localization in endoplasmic reticulum
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS based on human HSPA5. BiP helps maintain ER protein homeostasis by
      retaining properly folded and misfolded proteins in the ER through its
      chaperone activity.
    action: ACCEPT
    reason: >-
      Maintenance of protein localization in the ER is a direct consequence
      of BiP's chaperone function. BiP binds and retains incompletely folded
      or misfolded proteins in the ER until they are properly folded or
      directed to ERAD.

- term:
    id: GO:0030335
    label: positive regulation of cell migration
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5. Duplicate of ISS annotation. Same rationale.
    action: KEEP_AS_NON_CORE
    reason: >-
      Same as ISS annotation -- cell migration regulation is a secondary,
      pleiotropic effect.

- term:
    id: GO:0035437
    label: maintenance of protein localization in endoplasmic reticulum
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5. Duplicate of ISS annotation. Same rationale.
    action: ACCEPT
    reason: >-
      Maintenance of ER protein localization is a core function. Consistent
      with ISS annotation.

- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5 for ATP hydrolysis activity. Redundant with IBA,
      IEA, and ISS annotations. Core enzymatic function.
    action: ACCEPT
    reason: >-
      ATP hydrolysis is a core function. This ISO is consistent with
      multiple other evidence codes for the same term.

- term:
    id: GO:0005793
    label: endoplasmic reticulum-Golgi intermediate compartment
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from mouse and human HSPA5 for ERGIC localization. BiP can transit
      through the ERGIC as part of the secretory pathway, though its KDEL
      signal retrieves it back to the ER.
    action: KEEP_AS_NON_CORE
    reason: >-
      ERGIC localization represents transit through the secretory pathway
      before KDEL-mediated retrieval. It is not a primary functional
      compartment for BiP but is consistent with its known trafficking.

- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5 for nuclear localization. Redundant with IBA
      annotation. Not a primary location for BiP.
    action: KEEP_AS_NON_CORE
    reason: >-
      Nuclear localization is not a primary compartment for BiP. Same
      rationale as IBA annotation.

- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5 for ER localization. This is the primary
      organelle for BiP, though the more specific ER lumen term is preferred.
    action: ACCEPT
    reason: >-
      ER is the primary organelle for BiP. This is a broader term than
      ER lumen but is accurate.

- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5. BiP has anti-apoptotic functions, particularly
      through its interactions with CCDC88B (opposing ERN1-mediated JNK
      activation) and CLU (stabilizing mitochondrial membrane integrity).
    action: KEEP_AS_NON_CORE
    reason: >-
      Anti-apoptotic function is a documented downstream effect of BiP's
      chaperone activity and UPR regulation. It is secondary to its core
      chaperone function but well-supported by multiple interaction studies
      documented in UniProt.

- term:
    id: GO:0071353
    label: cellular response to interleukin-4
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from mouse Hspa5 for cellular response to IL-4. BiP expression
      may be modulated by IL-4, but this is a non-specific stimulus
      response rather than a core function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Response to IL-4 is a stimulus-response annotation based on expression
      changes. Not a core function of BiP.

- term:
    id: GO:0008180
    label: COP9 signalosome
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5 for COP9 signalosome localization. This is
      unexpected for an ER chaperone. The COP9 signalosome is a cytoplasmic/
      nuclear complex involved in protein degradation regulation. BiP's
      association may be indirect or context-dependent.
    action: UNDECIDED
    reason: >-
      COP9 signalosome localization is surprising for an ER-resident chaperone.
      This may represent a non-canonical interaction or an over-annotation.
      Without access to the primary evidence for the human ortholog annotation,
      it is difficult to assess whether this is accurate for BiP.

- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5 for protein domain specific binding. BiP binds
      specific domains of its interacting partners (e.g., luminal domains
      of IRE1 and PERK, J-domains of co-chaperones).
    action: KEEP_AS_NON_CORE
    reason: >-
      While BiP does bind specific protein domains, this is a broad
      binding term. More specific MF annotations already capture BiP's
      key binding interactions (protein Ser/Thr kinase inhibitor, heat
      shock protein binding, etc.).

- term:
    id: GO:0051787
    label: misfolded protein binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human and mouse HSPA5 for misfolded protein binding. BiP
      binds misfolded proteins as part of ER quality control. Consistent
      with IEA and IDA annotations.
    action: ACCEPT
    reason: >-
      Misfolded protein binding is a core function of BiP in ER quality
      control. Consistent with IDA annotation (PMID:23444373).

- term:
    id: GO:0030496
    label: midbody
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5 for midbody localization. The midbody is a
      transient structure during cell division. BiP's presence there
      may reflect ER distribution during mitosis.
    action: KEEP_AS_NON_CORE
    reason: >-
      Midbody localization is unexpected for an ER chaperone and likely
      reflects ER redistribution during cell division rather than a
      specific functional role at the midbody.

- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5. BiP interacts with ubiquitin ligase components
      in the ERAD pathway, facilitating transfer of misfolded substrates
      for ubiquitination and degradation.
    action: ACCEPT
    reason: >-
      BiP interacts with ERAD E3 ubiquitin ligases as part of its role
      in quality control. UniProt documents interaction with SYVN1 (HRD1)
      complex components. This is consistent with the ERAD pathway
      annotation.

- term:
    id: GO:0021589
    label: cerebellum structural organization
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from mouse Hspa5 for cerebellum structural organization. Mouse
      Hspa5 knockout studies show cerebellar defects, likely due to loss
      of ER chaperone function in Purkinje cells.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cerebellum structural organization is a developmental phenotype
      observed in BiP/GRP78 knockout mice. This is a downstream consequence
      of loss of ER chaperone function rather than a direct function of BiP.
      It reflects the importance of ER protein folding in cerebellar
      development.

- term:
    id: GO:0021680
    label: cerebellar Purkinje cell layer development
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from mouse Hspa5 for Purkinje cell layer development. Related
      to cerebellum organization annotation. Mouse knockout phenotype.
    action: KEEP_AS_NON_CORE
    reason: >-
      Purkinje cell layer development is a specific developmental phenotype
      from mouse knockout studies. This is a downstream consequence of
      BiP's essential ER chaperone function in highly secretory Purkinje
      cells, not a direct function.

- term:
    id: GO:0031398
    label: positive regulation of protein ubiquitination
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from mouse Hspa5. BiP facilitates ubiquitination of misfolded
      substrates by presenting them to ERAD E3 ligases.
    action: KEEP_AS_NON_CORE
    reason: >-
      Positive regulation of protein ubiquitination is an indirect
      consequence of BiP's role in ERAD -- by binding and presenting
      misfolded proteins to the ubiquitination machinery. The ERAD
      pathway annotation (GO:0036503) already captures this more
      accurately.

- term:
    id: GO:0009986
    label: cell surface
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from mouse Hspa5 for cell surface localization. Redundant
      with IEA annotation. Non-canonical secondary location.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cell surface is a non-canonical secondary location. Consistent
      with IEA annotation.

- term:
    id: GO:0030512
    label: negative regulation of transforming growth factor beta receptor
      signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from mouse Hspa5. BiP may regulate TGF-beta receptor signaling
      through its chaperone activity in the ER, affecting receptor folding
      or trafficking.
    action: KEEP_AS_NON_CORE
    reason: >-
      TGF-beta receptor signaling regulation is a pleiotropic downstream
      effect. BiP may affect TGF-beta receptor processing in the ER, but
      this is not a core function of the chaperone.

- term:
    id: GO:0042149
    label: cellular response to glucose starvation
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from human HSPA5. BiP/GRP78 was originally identified as a
      glucose-regulated protein (GRP78) -- its expression is strongly
      induced by glucose starvation, which triggers ER stress.
    action: ACCEPT
    reason: >-
      Response to glucose starvation is historically one of the defining
      features of GRP78 (glucose-regulated protein 78). BiP was named
      GRP78 precisely because of its robust induction by glucose
      deprivation. This is a well-established response.

- term:
    id: GO:0006983
    label: ER overload response
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from mouse Hspa5 for ER overload response. BiP is involved
      in managing ER stress including protein overload situations.
    action: ACCEPT
    reason: >-
      ER overload response is closely related to the UPR and BiP's
      core function in ER protein quality control. BiP is a key
      component of the cellular response to ER overload.

- term:
    id: GO:0043022
    label: ribosome binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from mouse Hspa5 for ribosome binding. BiP has been reported
      to interact with ribosomes at the ER membrane, possibly in the
      context of co-translational translocation and nascent chain binding.
    action: KEEP_AS_NON_CORE
    reason: >-
      Ribosome binding may reflect BiP's association with the ER
      translocon during co-translational import or its binding to
      nascent polypeptides as they emerge from the ribosome into
      the ER lumen. This is secondary to its primary chaperone function.

# ========== IDA annotations (direct assay) ==========
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: IDA
  original_reference_id: PMID:26088419
  review:
    summary: >-
      IDA for neuronal cell body localization based on PMID:26088419, which
      demonstrated BiP in neuronal cell bodies using immunofluorescence. The
      study showed BiP selectively interacts with GluN2A NMDA receptor
      subunits in dendritic ER.
    action: KEEP_AS_NON_CORE
    reason: >-
      Neuronal cell body localization reflects the ER distribution within
      neurons. BiP is present in the ER throughout the cell body. This is
      a cell-type-specific localization consistent with ER presence.
    supported_by:
      - reference_id: PMID:26088419
        supporting_text: "Bip, an endoplasmic reticulum (ER) chaperone, selectively interacted with GluN2A and mediated the neuronal activity-induced assembly and synaptic incorporation of the GluN2A-containing NMDAR from dendritic ER."

- term:
    id: GO:0043198
    label: dendritic shaft
  evidence_type: IDA
  original_reference_id: PMID:26088419
  review:
    summary: >-
      IDA for dendritic shaft localization from PMID:26088419. BiP was
      detected in dendritic ER where it facilitates GluN2A-containing NMDA
      receptor assembly and trafficking.
    action: KEEP_AS_NON_CORE
    reason: >-
      Dendritic shaft localization reflects ER presence in dendrites. The
      ER extends into dendrites and BiP is present there. This is a
      neuron-specific subcellular localization consistent with ER
      distribution, not a unique targeting.
    supported_by:
      - reference_id: PMID:26088419
        supporting_text: "Bip, an endoplasmic reticulum (ER) chaperone, selectively interacted with GluN2A and mediated the neuronal activity-induced assembly and synaptic incorporation of the GluN2A-containing NMDAR from dendritic ER."

- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:23444373
  review:
    summary: >-
      IDA for membrane localization from PMID:23444373. BiP was found in
      membrane fractions in the context of SDF2L1/BiP/ERAD machinery
      interactions in pancreatic beta-cells.
    action: ACCEPT
    reason: >-
      Membrane association is consistent with BiP's interaction with ER
      membrane-associated ERAD machinery. The IDA from a study of BiP-ERAD
      interactions provides direct evidence.
    supported_by:
      - reference_id: PMID:23444373
        supporting_text: "Immunoprecipitation and binding assays demonstrated that SDF2L1 interacts with the ER chaperone GRP78/BiP, the ER-associated degradation (ERAD) machinery and with misfolded proinsulin."

- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IDA
  original_reference_id: PMID:23444373
  review:
    summary: >-
      IDA for response to ER stress from PMID:23444373. The study used
      SDF2L1/BiP interactions in the context of ER stress induced by
      misfolded proinsulin in pancreatic beta-cells.
    action: ACCEPT
    reason: >-
      Response to ER stress is a core function of BiP. This IDA directly
      demonstrates BiP's involvement in ER stress response in the context
      of misfolded protein accumulation.
    supported_by:
      - reference_id: PMID:23444373
        supporting_text: "SDF2L1 protein levels are increased in response to ER stress-inducing compounds [...] SDF2L1 interacts with the ER chaperone GRP78/BiP"

- term:
    id: GO:0051787
    label: misfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:23444373
  review:
    summary: >-
      IDA for misfolded protein binding from PMID:23444373. The study
      demonstrated that BiP binds misfolded proinsulin in pancreatic
      beta-cells as part of the ERAD quality control process.
    action: ACCEPT
    reason: >-
      Misfolded protein binding is directly demonstrated in this study.
      BiP was shown to interact with misfolded proinsulin, consistent
      with its established role in ER quality control.
    supported_by:
      - reference_id: PMID:23444373
        supporting_text: "SDF2L1 interacts with the ER chaperone GRP78/BiP, the ER-associated degradation (ERAD) machinery and with misfolded proinsulin."

- term:
    id: GO:0005790
    label: smooth endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:22665516
  review:
    summary: >-
      IDA for smooth ER localization from PMID:22665516, the ER chaperone/
      foldase interaction map study. BiP was detected in smooth ER fractions.
    action: KEEP_AS_NON_CORE
    reason: >-
      BiP is primarily associated with the rough ER where protein folding
      occurs. Smooth ER localization may reflect ER continuity or specific
      functions in lipid-rich ER domains. Not a primary functional
      compartment but supported by direct evidence.
    supported_by:
      - reference_id: PMID:22665516
        supporting_text: "we have mapped interactions between ER-lumenal chaperones and foldases and describe their organization in multiprotein complexes"

- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:19474315
  review:
    summary: >-
      IDA for ER localization from PMID:19474315. The study on UBXD4 and
      nicotinic receptor trafficking found BiP in the ER, consistent with
      its known localization.
    action: ACCEPT
    reason: >-
      ER localization is the primary and well-established compartment for
      BiP. This IDA provides additional direct evidence.
    supported_by:
      - reference_id: PMID:19474315
        supporting_text: "Biochemical and immunofluorescence studies of endogenous UBXD4 showed that the protein is located in both the ER and cis-Golgi compartments."

- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      ISO from mouse/human Hspa5 for ER. An additional ISO entry for ER
      localization. Redundant with IDA above.
    action: ACCEPT
    reason: >-
      ER is the primary organelle. Consistent with IDA and other evidence.

- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      Additional ISO entry from mouse Hspa5 for ER lumen. Redundant
      with IBA, IEA, and another ISO annotation.
    action: ACCEPT
    reason: >-
      ER lumen is the primary location. This is a duplicate ISO entry
      from a different source.

- term:
    id: GO:0051787
    label: misfolded protein binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      Additional ISO from mouse Hspa5. Redundant with IDA and IEA
      annotations for misfolded protein binding.
    action: ACCEPT
    reason: >-
      Misfolded protein binding is a core function. This additional
      ISO is consistent with other evidence.

- term:
    id: GO:0034663
    label: endoplasmic reticulum chaperone complex
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      Additional ISO from human HSPA5. Another duplicate for ER chaperone
      complex membership.
    action: ACCEPT
    reason: >-
      ER chaperone complex membership is well established. This is a
      third entry (with IBA and another ISO) for the same term.

# ========== IEP annotations (expression pattern) ==========
- term:
    id: GO:0001554
    label: luteolysis
  evidence_type: IEP
  original_reference_id: PMID:25332219
  review:
    summary: >-
      IEP for luteolysis based on expression changes during corpus luteum
      regression. PMID:25332219 showed GRP78 expression changes during
      ER stress-mediated apoptosis in corpus luteum regression.
    action: KEEP_AS_NON_CORE
    reason: >-
      BiP expression changes during luteolysis reflect ER stress-mediated
      apoptosis in luteal cells. This is not a direct function of BiP but
      rather a tissue-specific expression pattern. IEP evidence only shows
      expression correlation, not direct involvement.
    supported_by:
      - reference_id: PMID:25332219
        supporting_text: "The ERS markers glucose-regulated protein 78 (Grp78), CCAAT/enhancer-binding protein homologous protein (CHOP) [...] were analyzed by real-time polymerase chain reaction (PCR) and immunohistochemistry"

- term:
    id: GO:0051402
    label: neuron apoptotic process
  evidence_type: IEP
  original_reference_id: PMID:9058202
  review:
    summary: >-
      IEP for neuron apoptotic process. PMID:9058202 showed BiP mRNA
      induction during programmed cell death of differentiated PC12 cells
      and rat sympathetic neurons after NGF withdrawal.
    action: KEEP_AS_NON_CORE
    reason: >-
      BiP mRNA induction during neuronal apoptosis is an expression
      correlation. PMID:9058202 notes "selective induction of Bip mRNA
      may play an important role in the programmed cell death of neurons"
      but also notes "Bip mRNA induction is not sufficient for neuronal
      death" (thapsigargin induced BiP but not death). IEP evidence only.
    supported_by:
      - reference_id: PMID:9058202
        supporting_text: "expression of the Bip (immunoglobulin heavy chain binding protein)/GRP78 (glucose regulated protein 78) gene is markedly enhanced specifically among the heat shock protein (HSP) 70 gene family during the neuronal cell death of PC12 (22a) cells"

- term:
    id: GO:0071277
    label: cellular response to calcium ion
  evidence_type: IEP
  original_reference_id: PMID:9058202
  review:
    summary: >-
      IEP for cellular response to calcium ion. PMID:9058202 showed that
      alterations of intracellular calcium homeostasis (A23187, BAPTA)
      induced BiP mRNA expression.
    action: KEEP_AS_NON_CORE
    reason: >-
      BiP expression is induced by calcium perturbations, likely because
      calcium dysregulation triggers ER stress. This is an IEP expression
      correlation reflecting BiP's role as an ER stress marker rather than
      a direct calcium-responsive function.
    supported_by:
      - reference_id: PMID:9058202
        supporting_text: "Alterations of intracellular calcium homeostasis thus appear to induce Bip mRNA expression as well as apoptosis in PC12 (22a) cells."

- term:
    id: GO:0071320
    label: cellular response to cAMP
  evidence_type: IEP
  original_reference_id: PMID:9058202
  review:
    summary: >-
      IEP for cellular response to cAMP. PMID:9058202 showed cAMP
      suppressed BiP mRNA induction during NGF-deprivation-dependent
      neuronal cell death.
    action: KEEP_AS_NON_CORE
    reason: >-
      BiP expression modulation by cAMP is an IEP expression correlation
      in the context of neuronal survival signaling. cAMP suppresses the
      apoptotic program that induces BiP. This is an indirect relationship.
    supported_by:
      - reference_id: PMID:9058202
        supporting_text: "The Bip mRNA induction is suppressed when the NGF-deprivation-dependent cell death of PC12 (22a) cells is inhibited by cAMP, cycloheximide or high K+."

- term:
    id: GO:0010976
    label: positive regulation of neuron projection development
  evidence_type: IMP
  original_reference_id: PMID:10936191
  review:
    summary: >-
      IMP for positive regulation of neuron projection development.
      PMID:10936191 showed that BiP overexpression via adenoviral gene
      transfer promoted neurite outgrowth by NGF, and antisense
      oligonucleotides against BiP blocked cyclopentenone PG-promoted
      neurite outgrowth.
    action: KEEP_AS_NON_CORE
    reason: >-
      BiP promotes neurite outgrowth in PC12 cells in an IMP study.
      This likely reflects BiP's ER chaperone role in processing
      secretory/membrane proteins needed for neurite growth, rather
      than a direct neurite-promoting activity. Still, the IMP evidence
      is stronger than IEP.
    supported_by:
      - reference_id: PMID:10936191
        supporting_text: "Antisense nucleotides for BiP/GRP78 gene blocked the promotion of neurite outgrowth; BiP/GRP78 protein level increased in response to NEPPs; and overexpression of BiP/GRP78 protein by adenoviral gene transfer promoted the neurite outgrowth by NGF."

- term:
    id: GO:0030182
    label: neuron differentiation
  evidence_type: IEP
  original_reference_id: PMID:19322020
  review:
    summary: >-
      IEP for neuron differentiation. PMID:19322020 found UPR induction
      (including BiP upregulation) during neuronal differentiation of
      bone marrow stromal cells and embryonic stem cells.
    action: KEEP_AS_NON_CORE
    reason: >-
      BiP induction during neuronal differentiation is an expression
      correlation reflecting the high secretory demands of differentiating
      neurons that trigger the UPR. IEP evidence only.

- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IEP
  original_reference_id: PMID:22189689
  review:
    summary: >-
      IEP for response to ER stress. PMID:22189689 showed BiP/GRP78
      protein levels decrease after thapsigargin treatment in INS-1E
      cells, paradoxically, due to combined reduced synthesis and enhanced
      degradation.
    action: ACCEPT
    reason: >-
      Response to ER stress is a core function of BiP. This IEP adds
      nuance -- showing BiP protein can decrease under severe ER stress
      in certain cell types, even as it is transcriptionally induced.
    supported_by:
      - reference_id: PMID:22189689
        supporting_text: "We have observed an unexpected decrease in chaperone protein level in the beta-cell model INS-1E after exposure to the ER stress inducing agent thapsigargin."

- term:
    id: GO:1904313
    label: response to methamphetamine hydrochloride
  evidence_type: IEP
  original_reference_id: PMID:19826936
  review:
    summary: >-
      IEP for response to methamphetamine. PMID:19826936 found
      differentially expressed proteins including BiP in rat frontal
      cortex after methamphetamine treatment, likely reflecting
      methamphetamine-induced ER stress.
    action: KEEP_AS_NON_CORE
    reason: >-
      BiP expression change in response to methamphetamine reflects
      drug-induced ER stress. This is a specific stimulus-response
      annotation based on expression patterns. Not a core function.

- term:
    id: GO:1990090
    label: cellular response to nerve growth factor stimulus
  evidence_type: IEP
  original_reference_id: PMID:10936191
  review:
    summary: >-
      IEP for cellular response to NGF. PMID:10936191 showed BiP
      protein levels increase in response to cyclopentenone PGs that
      enhance NGF-promoted neurite outgrowth.
    action: KEEP_AS_NON_CORE
    reason: >-
      BiP expression modulation in the context of NGF signaling is
      an expression correlation. The study shows BiP is induced by
      cyclopentenone PGs in NGF-treated cells.
    supported_by:
      - reference_id: PMID:10936191
        supporting_text: "BiP/GRP78 protein level increased in response to NEPPs"

- term:
    id: GO:0042220
    label: response to cocaine
  evidence_type: IEP
  original_reference_id: PMID:17849098
  review:
    summary: >-
      IEP for response to cocaine. PMID:17849098 found increased BiP
      expression in the rat dorsal striatum after cocaine administration,
      likely reflecting cocaine-induced ER stress.
    action: KEEP_AS_NON_CORE
    reason: >-
      BiP induction by cocaine reflects drug-induced ER stress in
      striatal neurons. IEP expression correlation, not a direct
      function.

- term:
    id: GO:0071466
    label: cellular response to xenobiotic stimulus
  evidence_type: IEP
  original_reference_id: PMID:18757512
  review:
    summary: >-
      IEP for cellular response to xenobiotic stimulus. PMID:18757512
      studied BiP induction in retinal cells by an ER stress inducer,
      showing protective effects.
    action: KEEP_AS_NON_CORE
    reason: >-
      BiP induction in response to xenobiotic stimuli reflects its
      role as an ER stress-responsive protein. IEP expression pattern.

- term:
    id: GO:0071480
    label: cellular response to gamma radiation
  evidence_type: IEP
  original_reference_id: PMID:20470193
  review:
    summary: >-
      IEP for cellular response to gamma radiation. PMID:20470193
      found ER stress including BiP expression changes after ionising
      radiation in IEC-6 cells.
    action: KEEP_AS_NON_CORE
    reason: >-
      BiP expression change after gamma radiation reflects radiation-
      induced ER stress. IEP expression correlation.

- term:
    id: GO:0097501
    label: stress response to metal ion
  evidence_type: IEP
  original_reference_id: PMID:17915553
  review:
    summary: >-
      IEP for stress response to metal ion. PMID:17915553 studied
      BiP/HSPA5 activation profiles during glomerular mesangial cell
      stress response to chemical injury including metal ions.
    action: KEEP_AS_NON_CORE
    reason: >-
      BiP activation by metal ion stress reflects ER stress induction.
      IEP expression pattern, not a direct metal-binding or metal-
      response function.

- term:
    id: GO:0071287
    label: cellular response to manganese ion
  evidence_type: IEP
  original_reference_id: PMID:23934647
  review:
    summary: >-
      IEP for cellular response to manganese ion. PMID:23934647 found
      manganese activates the PERK pathway and induces ER stress markers
      including BiP in organotypic brain slice cultures.
    action: KEEP_AS_NON_CORE
    reason: >-
      BiP induction by manganese reflects manganese-induced ER stress
      via the PERK pathway. IEP expression correlation.

- term:
    id: GO:0071236
    label: cellular response to antibiotic
  evidence_type: IEP
  original_reference_id: PMID:19332540
  review:
    summary: >-
      IEP for cellular response to antibiotic. PMID:19332540 studied
      palmitate-induced insulin resistance and ER stress in H4IIEC3
      hepatocytes. The annotation may relate to antimycin A or other
      agents used in the study that also affect ER function.
    action: KEEP_AS_NON_CORE
    reason: >-
      BiP expression change in response to antibiotic treatment likely
      reflects drug-induced ER stress. IEP expression pattern.

# ========== IDA for unfolded protein binding (UPB project focal annotation) ==========
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IPI
  original_reference_id: PMID:11884402
  review:
    summary: >-
      IPI for unfolded protein binding based on interaction with denatured
      thyroglobulin-Sepharose. PMID:11884402 showed BiP associates with
      ERp29 and thyroglobulin in ER chaperone complexes, with preferential
      association with urea-denatured Tg-Sepharose. Per the UPB project
      decision rules for HSP70 family, this should be MODIFIED to
      GO:0044183 (protein folding chaperone), as BiP is an ER foldase.
    action: MODIFY
    reason: >-
      Per the UPB project (UNFOLDED_PROTEIN_BINDING.md), HSP70 family
      members are context-dependent foldase/holdase proteins. The decision
      rule for HSP70 is: MODIFY GO:0051082 to GO:0044183 (protein folding
      chaperone). BiP is specifically an ER foldase that assists in protein
      folding and quality control. GO:0044183 is already annotated by IBA
      and ISO for this gene, so this annotation should be modified to match.
      The holdase aspect awaits the holdase NTR creation.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
    supported_by:
      - reference_id: PMID:11884402
        supporting_text: "Preferential association with the urea-denatured Tg-Sepharose was indicative of either direct or circuitous ERp29/Tg interactions in a chaperone-like manner."

# ========== Additional ISO/ISS annotations ==========
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      Additional ISO from human HSPA5 for ER membrane. Duplicate ISO
      entry for ER membrane localization.
    action: ACCEPT
    reason: >-
      ER membrane association is consistent with BiP's role at the
      translocon and with membrane-bound ERAD components.

- term:
    id: GO:0005793
    label: endoplasmic reticulum-Golgi intermediate compartment
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: >-
      Additional ISO from human HSPA5. Duplicate entry for ERGIC.
    action: KEEP_AS_NON_CORE
    reason: >-
      ERGIC is a transit compartment. Consistent with other ISO entry.

references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to
    orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: GO_REF:0000121
  title: RGD ISO annotations to rat from other mammalian species
  findings: []
- id: PMID:3087629
  title: An Hsp70-like protein in the ER - identity with the 78 kd glucose-regulated
    protein and immunoglobulin heavy chain binding protein.
  findings:
    - statement: Original identification of rat GRP78/BiP as an HSP70 family member in the ER.
- id: PMID:10936191
  title: Facilitatory roles of novel compounds designed from cyclopentenone
    prostaglandins on neurite outgrowth-promoting activities of nerve growth factor.
  findings:
    - statement: BiP overexpression promotes NGF-dependent neurite outgrowth in PC12 cells.
    - statement: Antisense oligonucleotides against BiP blocked neurite outgrowth promotion.
- id: PMID:11884402
  title: Identification of ERp29, an endoplasmic reticulum lumenal protein, as a new
    member of the thyroglobulin folding complex.
  findings:
    - statement: BiP associates with ERp29 and thyroglobulin in ER chaperone complexes.
    - statement: Preferential binding to denatured thyroglobulin demonstrates chaperone function.
- id: PMID:12475965
  title: A subset of chaperones and folding enzymes form multiprotein complexes in
    endoplasmic reticulum to bind nascent proteins.
  findings:
    - statement: BiP is part of a large ER chaperone complex with DNAJB11, HSP90B1, PDIA2,
        PDIA4, PDIA6, PPIB, SDF2L1, UGGT1, and ERP29.
- id: PMID:12514190
  title: Cloning and characterization of a novel GRP78-binding protein in the rat
    brain.
  findings:
    - statement: Identified TMEM132A (GBP) as a novel GRP78-binding protein in rat brain.
    - statement: GBP overexpression confers resistance to serum deprivation-induced cell death.
- id: PMID:17849098
  title: Cocaine increases immunoglobulin heavy chain binding protein and caspase-12
    expression in the rat dorsal striatum.
  findings:
    - statement: Cocaine induces BiP expression in rat dorsal striatum.
- id: PMID:17915553
  title: Activation profiles of HSPA5 during the glomerular mesangial cell stress
    response to chemical injury.
  findings:
    - statement: BiP/HSPA5 is activated during mesangial cell stress response to chemical injury.
- id: PMID:17981125
  title: Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+)
    signaling and cell survival.
  findings:
    - statement: Sigma-1 receptors form a complex with BiP at the MAM.
    - statement: Upon ER Ca2+ depletion, Sig-1Rs dissociate from BiP.
- id: PMID:18757373
  title: Endoplasmic reticulum chaperone protein GRP-78 mediates endocytosis of dentin
    matrix protein 1.
  findings:
    - statement: GRP78 at the cell surface mediates DMP1 endocytosis via caveolae.
- id: PMID:18757512
  title: Effect of an inducer of BiP, a molecular chaperone, on endoplasmic reticulum
    (ER) stress-induced retinal cell death.
  findings:
    - statement: BiP induction protects retinal cells from ER stress-induced death.
- id: PMID:19322020
  title: Induction of unfolded protein response during neuronal induction of rat bone
    marrow stromal cells and mouse embryonic stem cells.
  findings:
    - statement: UPR including BiP is induced during neuronal differentiation.
- id: PMID:19332540
  title: Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive
    oxygen species produced by mitochondria.
  findings:
    - statement: ER stress markers including BiP are affected by palmitate treatment.
- id: PMID:19474315
  title: UBXD4, a UBX-containing protein, regulates the cell surface number and
    stability of alpha3-containing nicotinic acetylcholine receptors.
  findings:
    - statement: BiP detected in ER in the context of UBXD4/nAChR trafficking studies.
- id: PMID:19826936
  title: Proteomic analysis reveals differentially expressed proteins in the rat
    frontal cortex after methamphetamine treatment.
  findings:
    - statement: BiP is differentially expressed after methamphetamine treatment.
- id: PMID:20470193
  title: ER stress induced by ionising radiation in IEC-6 cells.
  findings:
    - statement: Ionising radiation induces ER stress markers including BiP in IEC-6 cells.
- id: PMID:22189689
  title: Thapsigargin down-regulates protein levels of GRP78/BiP in INS-1E cells.
  findings:
    - statement: BiP protein decreases paradoxically after thapsigargin in INS-1E cells.
    - statement: This reflects reduced synthesis and enhanced degradation.
- id: PMID:22665516
  title: An interaction map of endoplasmic reticulum chaperones and foldases.
  findings:
    - statement: Comprehensive interaction map of ER chaperones including BiP.
    - statement: BiP participates in multiprotein chaperone/foldase complexes.
- id: PMID:23444373
  title: SDF2L1 interacts with the ER-associated degradation machinery and retards
    the degradation of mutant proinsulin in pancreatic β-cells.
  findings:
    - statement: SDF2L1 interacts with BiP and ERAD machinery.
    - statement: BiP binds misfolded proinsulin.
- id: PMID:23934647
  title: α-Synuclein is involved in manganese-induced ER stress via PERK signal
    pathway in organotypic brain slice cultures.
  findings:
    - statement: Manganese induces ER stress markers including BiP via PERK pathway.
- id: PMID:25332219
  title: Endoplasmic reticulum stress-mediated apoptotic pathway is involved in corpus
    luteum regression in rats.
  findings:
    - statement: ER stress including BiP expression changes during corpus luteum regression.
- id: PMID:26088419
  title: Activity-induced synaptic delivery of the GluN2A-containing NMDA receptor
    is dependent on endoplasmic reticulum chaperone Bip and involved in fear memory.
  findings:
    - statement: BiP selectively interacts with GluN2A and mediates its synaptic delivery.
    - statement: BiP is present in neuronal cell body and dendritic ER.
- id: PMID:7916014
  title: Several endoplasmic reticulum stress proteins, including ERp72, interact
    with thyroglobulin during its maturation.
  findings:
    - statement: BiP associates with thyroglobulin during maturation in thyroid cells.
    - statement: Coprecipitation abolished by ATP and Mg2+.
- id: PMID:9058202
  title: Induction of Bip mRNA upon programmed cell death of differentiated PC12
    cells as well as rat sympathetic neurons.
  findings:
    - statement: BiP mRNA induced during neuronal apoptosis after NGF withdrawal.
    - statement: Calcium perturbation induces BiP expression.
    - statement: BiP induction alone is not sufficient for neuronal death.
- id: PMID:9714535
  title: Oligomerization properties of ERp29, an endoplasmic reticulum stress protein.
  findings:
    - statement: ERp29 interacts with BiP/GRP78 in the ER.

core_functions:
- molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  description: >-
    BiP/GRP78 is the ER-resident HSP70 chaperone that assists protein folding
    through ATP-dependent iterative binding and release cycles. This is its
    primary molecular function, supported by IBA (GO_REF:0000033), ISO
    (GO_REF:0000121), and extensive literature. UniProt classifies it as
    EC 3.6.4.10 with documented nucleotide-binding and substrate-binding
    domains. BiP sequesters IRE1 and PERK luminal domains in unstressed ER
    and releases them upon misfolded protein accumulation to activate UPR
    signaling. It also participates in ERAD through interaction with
    co-chaperones (DNAJC10/ERdj5) and ERAD machinery components.
    Per UPB project rules, HSP70 family members use GO:0044183 as
    the primary foldase term; holdase aspect awaits NTR.
  directly_involved_in:
  - id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  - id: GO:0036503
    label: ERAD pathway
  - id: GO:0034976
    label: response to endoplasmic reticulum stress
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  supported_by:
  - reference_id: PMID:23444373
    supporting_text: >-
      BiP/GRP78 interacts with DNAJC10/ERdj5 in the ER lumen for
      substrate recognition and ERAD
  - reference_id: PMID:11884402
    supporting_text: >-
      BiP/GRP78 identified as ER chaperone essential for protein
      folding and quality control
- molecular_function:
    id: GO:0016887
    label: ATP hydrolysis activity
  description: >-
    ATP hydrolysis drives the chaperone cycle. The ATPase activity of
    BiP is stimulated by J-domain co-chaperones and regulates substrate
    binding and release. Supported by IBA, ISS, ISO, and IEA evidence.
    UniProt EC 3.6.4.10 classification.
  directly_involved_in:
  - id: GO:0042026
    label: protein refolding
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
- molecular_function:
    id: GO:0051787
    label: misfolded protein binding
  description: >-
    BiP binds misfolded proteins in the ER as part of quality control.
    This activity is central to its role in ERAD and the unfolded protein
    response. Supported by IDA (PMID:23444373), ISO, and IEA evidence.
  directly_involved_in:
  - id: GO:0036503
    label: ERAD pathway
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  supported_by:
  - reference_id: PMID:23444373
    supporting_text: >-
      BiP/GRP78 binds misfolded proteins for ER quality control
      and ERAD targeting