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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:rat/Hspa5/Hspa5-deep-research-falcon.md Under stress, HSPA5/GRP78 can relocalize beyond the ER, including **cell surface**, and some reviews note presence in mitochondria/nucleus/secreted pools depending on context. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: UniProtKB:P06761 Cytoplasm {ECO:0000250|UniProtKB:P20029} |
| GO:0016887 ATP hydrolysis activity | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: GO_REF:0000033 IBA from phylogenetic inference across HSP70 family members with demonstrated ATPase activity file:rat/Hspa5/Hspa5-deep-research-falcon.md BiP is an **ATP-dependent molecular chaperone** with an **N-terminal nucleotide/ATPase-binding domain** and **C-terminal substrate-binding domain** that binds unfolded polypeptides, maintains folding competence, and prevents aggregation. |
| GO:0031072 heat shock protein binding | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:22665516 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. |
| GO:0044183 protein folding chaperone | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:rat/Hspa5/Hspa5-deep-research-falcon.md **BiP/GRP78 (Hspa5/HSPA5)** is the major **ER-resident HSP70-family chaperone** that binds nascent/unfolded proteins in the ER lumen, maintaining them in a folding-competent state and supporting folding, oligomerization, and post-translational maturation. file:rat/Hspa5/Hspa5-deep-research-falcon.md BiP is an **ATP-dependent** chaperone whose substrate binding and release are controlled by a **nucleotide/ATPase cycle**, with an N-terminal **nucleotide-binding (ATPase) domain** functionally coupled to a C-terminal **substrate-binding domain**. |
| GO:0036503 ERAD quality control pathway | IBA GO_REF:0000033 | ACCEPT | 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). 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. Supporting Evidence: PMID:23444373 SDF2L1 interacts with the ER chaperone GRP78/BiP, the ER-associated degradation (ERAD) machinery and with misfolded proinsulin. file:rat/Hspa5/Hspa5-deep-research-falcon.md BiP is central to **ER proteostasis**, recognizing unfolded/misfolded proteins and contributing to **ERAD-linked quality control** and broader degradation routing. |
| GO:0016020 membrane | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | 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. Reason: BiP is a soluble ER-lumenal protein (signal peptide plus C-terminal KDEL retention motif) with no membrane-spanning domain. The generic "membrane" term is uninformative and potentially misleading. Its transient membrane association during translocation and its non-canonical cell-surface pool are already captured by the more specific ER membrane (GO:0005789) and plasma membrane (GO:0005886) annotations, which are retained. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN001834223 Β· PTN001834223 SUPPORTS TRANSFER The current PTHR19375 PAINT slice places the GO:0016020 IBD at this BiP-specific node (eukaryote-scoped, snapshot 2023-01-11), whose seeds are all BiP orthologs - mouse Hspa5 (MGI:95835), human HSPA5 (P11021), S. pombe bip1, rice Q6Z7B0, and rat Hspa5 itself (RGD:2843). It is not a generic HSP70 leak, and the same node carries the ER lumen, ER chaperone complex, UPR and ERAD assertions this review accepts, so the node placement is sound and the target sits squarely inside the clade. Rat's own curated IDA to membrane (PMID:23444373) is one of the descendant evidences behind the node, which marks experimental grounding on the target rather than circular support. The remaining objection is purely one of term scoping - for a soluble ER-lumenal KDEL protein whose membrane contact is peripheral (translocon-associated), the bare membrane term adds nothing over the retained ER membrane (GO:0005789) and plasma membrane (GO:0005886) rows. Supporting Evidence: file:rat/Hspa5/Hspa5-deep-research-falcon.md BiP is primarily localized to the **ER lumen**, and ER retention depends on the **C-terminal KDEL** retrieval motif and KDEL receptor (KDELR)-mediated retrieval between ER and Golgi. |
| GO:0042026 protein refolding | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: UniProtKB:P06761 Endoplasmic reticulum chaperone that plays a key role in protein folding and quality control in the endoplasmic reticulum lumen UniProtKB:P06761 in the ATP-bound state the two domains are tightly coupled, which results in drastically accelerated kinetics in both binding and release of polypeptide substrates |
| GO:0034663 endoplasmic reticulum chaperone complex | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:22665516 we have mapped interactions between ER-lumenal chaperones and foldases and describe their organization in multiprotein complexes |
| GO:0005788 endoplasmic reticulum lumen | IBA GO_REF:0000033 | ACCEPT | 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). 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. Supporting Evidence: file:rat/Hspa5/Hspa5-deep-research-falcon.md BiP is primarily localized to the **ER lumen**, and ER retention depends on the **C-terminal KDEL** retrieval motif and KDEL receptor (KDELR)-mediated retrieval between ER and Golgi. |
| GO:0030968 endoplasmic reticulum unfolded protein response | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:rat/Hspa5/Hspa5-deep-research-falcon.md BiP negatively regulates the three canonical UPR sensors **IRE1, PERK, and ATF6** under basal conditions; ER stress sequesters BiP onto misfolded proteins, allowing sensor activation. file:rat/Hspa5/Hspa5-deep-research-falcon.md A key in vivo interactome study provides direct evidence that BiP binds **IRE1Ξ± and PERK** under basal conditions and is released upon pharmacologic ER stress (tunicamycin), consistent with the canonical activation model. |
| GO:0000166 nucleotide binding | IEA GO_REF:0000043 | ACCEPT | 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. 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. GOA no longer carries this annotation (retired at the 2026 GOA refresh); the review is kept for provenance. |
| GO:0005524 ATP binding | IEA GO_REF:0000120 | ACCEPT | 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. 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. GOA no longer carries this annotation (retired at the 2026 GOA refresh); the review is kept for provenance. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: IEA from UniProt subcellular location mapping. Duplicate of the IBA annotation for cytoplasm. UniProt lists cytoplasm as a subcellular location. Reason: Cytoplasmic localization is secondary to ER lumen. Acceptable as a broader IEA that is consistent with the IBA annotation. Supporting Evidence: UniProtKB:P06761 Cytoplasm {ECO:0000250|UniProtKB:P20029} |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from UniProt subcellular location mapping for ER lumen. Duplicates the IBA annotation. ER lumen is the primary location of BiP. 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. Supporting Evidence: UniProtKB:P06761 SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0009986 cell surface | IEA GO_REF:0000044 | KEEP AS NON CORE | 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. 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. Supporting Evidence: UniProtKB:P06761 Localizes to the cell surface in epithelial cells; high levels of free iron promotes cell surface localization |
| GO:0016787 hydrolase activity | IEA GO_REF:0000043 | ACCEPT | 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. 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. GOA no longer carries this annotation (retired at the 2026 GOA refresh); the review is kept for provenance. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA from InterPro/RHEA mapping for ATP hydrolysis activity. Duplicates the IBA annotation. BiP is classified as EC 3.6.4.10. Reason: ATP hydrolysis activity is a core function of BiP, consistent with the IBA annotation and the EC classification. Supporting Evidence: UniProtKB:P06761 Reaction=ATP + H2O = ADP + phosphate + H(+) |
| GO:0034976 response to endoplasmic reticulum stress | IEA GO_REF:0000117 | ACCEPT | 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. 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. Supporting Evidence: UniProtKB:P06761 Acts as a key repressor of the EIF2AK3/PERK and ERN1/IRE1-mediated unfolded protein response (UPR) |
| GO:0042470 melanosome | IEA GO_REF:0000044 | KEEP AS NON CORE | 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. 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. Supporting Evidence: UniProtKB:P06761 Identified by mass spectrometry in melanosome fractions from stage I to stage IV |
| GO:0051787 misfolded protein binding | IEA GO_REF:0000117 | ACCEPT | 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. 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. Supporting Evidence: file:rat/Hspa5/Hspa5-deep-research-falcon.md BiP is central to **ER proteostasis**, recognizing unfolded/misfolded proteins and contributing to **ERAD-linked quality control** and broader degradation routing. |
| GO:0005515 protein binding | IPI PMID:17981125 Sigma-1 receptor chaperones at the ER-mitochondrion interfac... | REMOVE | 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. Reason: GO:0005515 protein binding conveys no functional information. The cited study (abstract-only in cache) shows that the Sigma-1 receptor forms a complex with BiP at the mitochondrion-associated ER membrane and dissociates from it on ER Ca2+ depletion or ligand stimulation. This is a regulated interaction in which the Sigma-1 receptor is the active chaperone, but it does not establish a specific BiP molecular function that could replace the generic term. Removal reflects that the generic term is uninformative; it does not mean the reported interaction is false. Supporting Evidence: PMID:17981125 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. |
| GO:0005515 protein binding | IPI PMID:7916014 Several endoplasmic reticulum stress proteins, including ERp... | MODIFY | 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. Reason: Generic protein binding is uninformative. The cited study shows ATP-sensitive association of BiP with its maturing client thyroglobulin in thyroid cells (coprecipitation is abolished by ATP and Mg2+, and binding to denatured thyroglobulin is reversed by ATP), which is the client-binding step of the BiP chaperone cycle. GO:0044183 protein folding chaperone describes that activity, and it is the term curators now use for the same BiP-thyroglobulin interaction from PMID:11884402 (GO:0044183 IPI with RGD:3848, thyroglobulin). Proposed replacements: protein folding chaperone Supporting Evidence: PMID:7916014 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. PMID:7916014 several endoplasmic reticulum (ER) proteins, including BiP, ERp72, grp94, and protein disulfide isomerase, bind to a denatured thyroglobulin (Tg) affinity column and can be specifically eluted by ATP |
| GO:0005515 protein binding | IPI PMID:18757373 Endoplasmic reticulum chaperone protein GRP-78 mediates endo... | REMOVE | 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. Reason: Generic protein binding is uninformative. The cited study (abstract-only in cache) reports specific, saturable binding of DMP1 to a plasma-membrane GRP78 pool that initiates DMP1 endocytosis in preodontoblasts. This is a non-canonical, context-specific role, and the abstract does not define a receptor activity for BiP precisely enough to assert a replacement molecular function. Removal reflects that the generic term is uninformative; it does not mean the reported interaction is false. GOA no longer carries this annotation (retired at the 2026 GOA refresh); the review is kept for provenance. Supporting Evidence: PMID:18757373 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. |
| GO:0005515 protein binding | IPI PMID:9714535 Oligomerization properties of ERp29, an endoplasmic reticulu... | REMOVE | 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. Reason: Generic protein binding is uninformative. The cited study detects BiP among ER proteins cross-linked to ERp29 in rat hepatoma cells, which reflects co-residence in ER chaperone assemblies (captured by GO:0034663 endoplasmic reticulum chaperone complex) but does not identify a specific BiP activity toward ERp29. Removal reflects that the generic term is uninformative; it does not mean the reported interaction is false. Supporting Evidence: PMID:9714535 ERp29 interacts with a number of ER proteins, one of which was previously identified as BiP/GRP78. |
| GO:0005515 protein binding | IPI PMID:12514190 Cloning and characterization of a novel GRP78-binding protei... | REMOVE | 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. Reason: Generic protein binding is uninformative. The study identified GRP78 as a partner of GBP/TMEM132A by GST pull-down from PC12 lysates, which establishes physical association but no specific BiP activity toward TMEM132A that could replace the generic term. Removal reflects that the generic term is uninformative; it does not mean the reported interaction is false. GOA no longer carries this annotation (retired at the 2026 GOA refresh); the review is kept for provenance. Supporting Evidence: PMID:12514190 we performed a GST-tagged GBP pull-down assay in PC12 lysates and identified GRP78, one of the heat shock proteins, as a counterpart. |
| GO:0005788 endoplasmic reticulum lumen | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from RGD based on human HSPA5 (P11021). ER lumen is the primary subcellular location for BiP. Consistent with IBA and IEA annotations. 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. Supporting Evidence: UniProtKB:P06761 SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0140311 protein sequestering activity | ISO GO_REF:0000121 | ACCEPT | 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. 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. Supporting Evidence: UniProtKB:P06761 In the unstressed endoplasmic reticulum, recruited by DNAJB9/ERdj4 to the luminal region of ERN1/IRE1, leading to disrupt the dimerization of ERN1/IRE1, thereby inactivating ERN1/IRE1 UniProtKB:P06761 Also binds and inactivates EIF2AK3/PERK in unstressed cells |
| GO:1903894 regulation of IRE1-mediated unfolded protein response | ISO GO_REF:0000121 | ACCEPT | 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. 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." Supporting Evidence: file:rat/Hspa5/Hspa5-deep-research-falcon.md A key in vivo interactome study provides direct evidence that BiP binds **IRE1Ξ± and PERK** under basal conditions and is released upon pharmacologic ER stress (tunicamycin), consistent with the canonical activation model. |
| GO:0030291 protein serine/threonine kinase inhibitor activity | ISO GO_REF:0000121 | ACCEPT | 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. 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. Supporting Evidence: UniProtKB:P06761 Interacts with EIF2AK3/PERK (via luminal domain); interaction leads to inactivate EIF2AK3/PERK |
| GO:1903898 negative regulation of PERK-mediated unfolded protein response | ISO GO_REF:0000121 | ACCEPT | 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. 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." Supporting Evidence: file:rat/Hspa5/Hspa5-deep-research-falcon.md BiP negatively regulates the three canonical UPR sensors **IRE1, PERK, and ATF6** under basal conditions; ER stress sequesters BiP onto misfolded proteins, allowing sensor activation. |
| GO:0044183 protein folding chaperone | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from mouse Hspa5 (MGI:95835) for protein folding chaperone activity. Redundant with the IBA annotation. This is the core molecular function. Reason: Protein folding chaperone is the core MF for BiP. This ISO is consistent with the IBA and with UniProt functional description. Supporting Evidence: UniProtKB:P06761 Endoplasmic reticulum chaperone that plays a key role in protein folding and quality control in the endoplasmic reticulum lumen |
| GO:0016887 ATP hydrolysis activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS based on C. elegans BiP ortholog (G3I8R9) for ATP hydrolysis activity. Redundant with IBA and IEA annotations. Core enzymatic function. Reason: ATP hydrolysis is a core function. This ISS is consistent with other evidence codes for the same term. Supporting Evidence: UniProtKB:P06761 Reaction=ATP + H2O = ADP + phosphate + H(+) |
| GO:0031333 negative regulation of protein-containing complex assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | 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. 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. Supporting Evidence: UniProtKB:P06761 In the unstressed endoplasmic reticulum, recruited by DNAJB9/ERdj4 to the luminal region of ERN1/IRE1, leading to disrupt the dimerization of ERN1/IRE1, thereby inactivating ERN1/IRE1 |
| GO:0005524 ATP binding | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from human HSPA5 for ATP binding. Redundant with IEA annotation. Core function with well-documented binding sites in UniProt. Reason: ATP binding is fundamental to BiP's chaperone cycle. UniProt documents multiple ATP binding sites. Consistent with other evidence codes. Supporting Evidence: UniProtKB:P06761 in the ATP-bound state the two domains are tightly coupled, which results in drastically accelerated kinetics in both binding and release of polypeptide substrates |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO from human HSPA5 for cytoplasm. Redundant with IBA and IEA annotations. Secondary localization. Reason: Cytoplasm is a secondary localization for BiP. Consistent with other evidence codes. Supporting Evidence: UniProtKB:P06761 Cytoplasm {ECO:0000250|UniProtKB:P20029} |
| GO:0031204 post-translational protein targeting to membrane, translocation | ISS GO_REF:0000024 | ACCEPT | 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)." 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. Supporting Evidence: UniProtKB:P06761 May function as an allosteric modulator for SEC61 channel-forming translocon complex, likely cooperating with SEC62 to enable the productive insertion of these precursors into SEC61 channel |
| GO:0031204 post-translational protein targeting to membrane, translocation | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from human HSPA5. Duplicate of the ISS annotation for the same process. Same rationale applies. Reason: Post-translational translocation is a documented function of BiP. This ISO is redundant with the ISS but uses different reference basis. Supporting Evidence: UniProtKB:P06761 May function as an allosteric modulator for SEC61 channel-forming translocon complex, likely cooperating with SEC62 to enable the productive insertion of these precursors into SEC61 channel |
| GO:0005739 mitochondrion | ISO GO_REF:0000121 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:17981125 Sig-1Rs form a complex at MAM with another chaperone, BiP. |
| GO:0005829 cytosol | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS based on human HSPA5 for cytosol localization. BiP may be released from ER to cytosol under stress conditions or during apoptosis. Reason: Cytosolic localization is not a primary location for BiP. It may occur under stress or pathological conditions. Not a core compartment. Supporting Evidence: UniProtKB:P06761 Cytoplasm {ECO:0000250|UniProtKB:P20029} |
| GO:0005829 cytosol | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO from human HSPA5 for cytosol. Redundant with ISS annotation. Reason: Cytosol is not a primary location for BiP. Redundant with ISS annotation. Supporting Evidence: UniProtKB:P06761 Cytoplasm {ECO:0000250|UniProtKB:P20029} |
| GO:0036498 IRE1-mediated unfolded protein response | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from mouse Hspa5 for IRE1-mediated UPR. BiP is a central regulator of IRE1 signaling by binding its luminal domain. Reason: BiP's involvement in the IRE1 pathway is well established. This is related to but more specific than the general ER UPR annotation. Supporting Evidence: UniProtKB:P06761 In the unstressed endoplasmic reticulum, recruited by DNAJB9/ERdj4 to the luminal region of ERN1/IRE1, leading to disrupt the dimerization of ERN1/IRE1, thereby inactivating ERN1/IRE1 |
| GO:0030968 endoplasmic reticulum unfolded protein response | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from mouse Hspa5 for ER UPR. Redundant with IBA annotation. Core biological process for BiP. Reason: ER UPR is a core process for BiP. Consistent with IBA and other annotations. Supporting Evidence: UniProtKB:P06761 Acts as a key repressor of the EIF2AK3/PERK and ERN1/IRE1-mediated unfolded protein response (UPR) |
| GO:1903895 negative regulation of IRE1-mediated unfolded protein response | ISS GO_REF:0000024 | ACCEPT | 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. 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. Supporting Evidence: UniProtKB:P06761 In the unstressed endoplasmic reticulum, recruited by DNAJB9/ERdj4 to the luminal region of ERN1/IRE1, leading to disrupt the dimerization of ERN1/IRE1, thereby inactivating ERN1/IRE1 |
| GO:0032991 protein-containing complex | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO from human HSPA5 for protein-containing complex. Very broad localization term. BiP forms multiple complexes in the ER. 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. Supporting Evidence: UniProtKB:P06761 Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29 |
| GO:0034663 endoplasmic reticulum chaperone complex | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from mouse and human HSPA5. Redundant with IBA annotation for ER chaperone complex. Core complex membership. Reason: ER chaperone complex is a well-documented localization. Consistent with IBA annotation. Supporting Evidence: UniProtKB:P06761 Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29 |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | KEEP AS NON CORE | 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. 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." The falcon synthesis frames cell-surface GRP78 (csGRP78) as a stress-induced, context-specific signaling/attachment factor distinct from the core ER chaperone function. Supporting Evidence: file:rat/Hspa5/Hspa5-deep-research-falcon.md **Cell-surface GRP78 (csGRP78)** acts as a signaling/attachment factor linked to cancer survival/therapy resistance and can serve as a **viral attachment/pro-viral factor**. |
| GO:0005789 endoplasmic reticulum membrane | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from mouse and human HSPA5 for ER membrane localization. BiP associates with ER membranes through its interaction with the SEC61 translocon complex. 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. Supporting Evidence: UniProtKB:P06761 May function as an allosteric modulator for SEC61 channel-forming translocon complex, likely cooperating with SEC62 to enable the productive insertion of these precursors into SEC61 channel |
| GO:0019899 enzyme binding | ISO GO_REF:0000121 | KEEP AS NON CORE | 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. 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. Supporting Evidence: UniProtKB:P06761 Interacts with EIF2AK3/PERK (via luminal domain); interaction leads to inactivate EIF2AK3/PERK |
| GO:0030335 positive regulation of cell migration | ISS GO_REF:0000024 | KEEP AS NON CORE | 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." 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. Supporting Evidence: UniProtKB:P06761 Interacts with CEMIP; the interaction induces calcium leakage from the endoplasmic reticulum and cell migration |
| GO:0035437 maintenance of protein localization in endoplasmic reticulum | ISS GO_REF:0000024 | ACCEPT | 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. 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. Supporting Evidence: UniProtKB:P06761 Endoplasmic reticulum chaperone that plays a key role in protein folding and quality control in the endoplasmic reticulum lumen |
| GO:0030335 positive regulation of cell migration | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO from human HSPA5. Duplicate of ISS annotation. Same rationale. Reason: Same as ISS annotation -- cell migration regulation is a secondary, pleiotropic effect. Supporting Evidence: UniProtKB:P06761 Interacts with CEMIP; the interaction induces calcium leakage from the endoplasmic reticulum and cell migration |
| GO:0035437 maintenance of protein localization in endoplasmic reticulum | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from human HSPA5. Duplicate of ISS annotation. Same rationale. Reason: Maintenance of ER protein localization is a core function. Consistent with ISS annotation. Supporting Evidence: UniProtKB:P06761 Endoplasmic reticulum chaperone that plays a key role in protein folding and quality control in the endoplasmic reticulum lumen |
| GO:0016887 ATP hydrolysis activity | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from human HSPA5 for ATP hydrolysis activity. Redundant with IBA, IEA, and ISS annotations. Core enzymatic function. Reason: ATP hydrolysis is a core function. This ISO is consistent with multiple other evidence codes for the same term. Supporting Evidence: UniProtKB:P06761 Reaction=ATP + H2O = ADP + phosphate + H(+) |
| GO:0005793 endoplasmic reticulum-Golgi intermediate compartment | ISO GO_REF:0000121 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:rat/Hspa5/Hspa5-deep-research-falcon.md BiP is primarily localized to the **ER lumen**, and ER retention depends on the **C-terminal KDEL** retrieval motif and KDEL receptor (KDELR)-mediated retrieval between ER and Golgi. |
| GO:0005634 nucleus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO from human HSPA5 for nuclear localization. Redundant with IBA annotation. Not a primary location for BiP. Reason: Nuclear localization is not a primary compartment for BiP. Same rationale as IBA annotation. Supporting Evidence: file:rat/Hspa5/Hspa5-deep-research-falcon.md Under stress, HSPA5/GRP78 can relocalize beyond the ER, including **cell surface**, and some reviews note presence in mitochondria/nucleus/secreted pools depending on context. |
| GO:0005783 endoplasmic reticulum | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from human HSPA5 for ER localization. This is the primary organelle for BiP, though the more specific ER lumen term is preferred. Reason: ER is the primary organelle for BiP. This is a broader term than ER lumen but is accurate. Supporting Evidence: UniProtKB:P06761 SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0043066 negative regulation of apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | 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). 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. Supporting Evidence: UniProtKB:P06761 the interaction opposes ERN1-mediated JNK activation, protecting against apoptosis PMID:19816510 GRP78-depleted PCs activate UPR including the induction of GRP94, PDI, CHOP and GADD34, feedback suppression of eIF2alpha phosphorylation and apoptotic cell death. |
| GO:0071353 cellular response to interleukin-4 | ISO GO_REF:0000121 | KEEP AS NON CORE | 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. Reason: Response to IL-4 is a stimulus-response annotation based on expression changes. Not a core function of BiP. Supporting Evidence: PMID:9798653 we used a sensitive PCR-based subtraction approach to isolate genes expressed in IL-4 treated cells |
| GO:0008180 COP9 signalosome | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ISO from human HSPA5 for COP9 signalosome localization. This is unexpected for an ER chaperone. The COP9 signalosome is a cytoplasmic/ nuclear deneddylation complex involved in regulating cullin-RING ubiquitin ligases. An ER-luminal HSP70 chaperone retained by a KDEL motif is not a plausible structural component of this complex. The falcon synthesis keeps BiP localization firmly ER-centric (ER lumen, with stress-induced cell- surface/secreted pools) and does not implicate it in the COP9 signalosome. Reason: COP9 signalosome (a cytoplasmic/nuclear complex) is incompatible with the topology and KDEL-dependent ER-lumen retention of BiP/GRP78. This CC annotation, transferred by ISO, most likely reflects high-abundance co-purification of BiP rather than genuine membership of the COP9 signalosome, and is best treated as an over-annotation. Recent synthesis describes non-canonical BiP pools (cell surface, secreted) under stress but not COP9 signalosome residency. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH SOURCE EVIDENCE WEAK Sources checked: UniProtKB:P11021 Β· human HSPA5 SUPPORTS SOURCE BUT NOT TARGET Sole ISO donor. The human COP9-signalosome association most likely reflects high-abundance co-purification of BiP in complex proteomics rather than genuine subunit membership, and a cytoplasmic/nuclear complex is incompatible with BiP's KDEL-retained ER-lumenal topology; unsafe to transfer to rat as a compartment claim. Supporting Evidence: file:rat/Hspa5/Hspa5-deep-research-falcon.md BiP is primarily localized to the **ER lumen**, and ER retention depends on the **C-terminal KDEL** retrieval motif and KDEL receptor (KDELR)-mediated retrieval between ER and Golgi. |
| GO:0019904 protein domain specific binding | ISO GO_REF:0000121 | KEEP AS NON CORE | 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). 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.). Supporting Evidence: PMID:12411443 ERdj5 interacts via its DnaJ domain with BiP in an ATP-dependent manner. |
| GO:0051787 misfolded protein binding | ISO GO_REF:0000121 | ACCEPT | 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. Reason: Misfolded protein binding is a core function of BiP in ER quality control. Consistent with IDA annotation (PMID:23444373). |
| GO:0030496 midbody | ISO GO_REF:0000121 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:15166316 used a functional proteomic and comparative genomic strategy. |
| GO:0031625 ubiquitin protein ligase binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO from human HSPA5 (P11021). The human source is an IPI from PMID:8666824, a study of the Ro/SS-A ribonucleoprotein that includes the 52-kDa component Ro52/TRIM21, an E3 ubiquitin ligase; UniProt records interaction of BiP with TRIM21. Reason: Binding of an E3 ubiquitin ligase (TRIM21) is a documented but peripheral interaction, not part of the core BiP chaperone cycle; the source abstract is cached without full text, so the annotation is kept on the curator's authority. An earlier version of this review attributed the row to binding of the SYVN1/HRD1 ERAD ligase complex, which is not what the source reports. BiP's ERAD role is captured separately by GO:0036503. Supporting Evidence: UniProtKB:P06761 Interacts with TMEM132A and TRIM21 |
| GO:0021589 cerebellum structural organization | ISO GO_REF:0000121 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:19816510 The mice show retarded growth and severe motor coordination defect by week 5 and cerebellar atrophy by week 13. |
| GO:0021680 cerebellar Purkinje cell layer development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO from mouse Hspa5 for Purkinje cell layer development. Related to cerebellum organization annotation. Mouse knockout phenotype. 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. Supporting Evidence: PMID:19816510 GRP78/BiP, a major ER chaperone and master regulator of UPR, is specifically eliminated in Purkinje cells (PCs). |
| GO:0031398 positive regulation of protein ubiquitination | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO from mouse Hspa5. BiP facilitates ubiquitination of misfolded substrates by presenting them to ERAD E3 ligases. 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. Supporting Evidence: PMID:19816510 cytosolic ubiquitin staining is dramatically reduced in GRP78-null PCs. |
| GO:0009986 cell surface | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO from mouse Hspa5 for cell surface localization. Redundant with IEA annotation. Non-canonical secondary location. Reason: Cell surface is a non-canonical secondary location. Consistent with IEA annotation. Supporting Evidence: UniProtKB:P06761 Localizes to the cell surface in epithelial cells; high levels of free iron promotes cell surface localization |
| GO:0030512 negative regulation of transforming growth factor beta receptor signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO from mouse Hspa5. BiP may regulate TGF-beta receptor signaling through its chaperone activity in the ER, affecting receptor folding or trafficking. 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. Supporting Evidence: PMID:17991893 Interestingly, short hairpin RNA knockdown of endogenous GRP78 resulted in enhanced transforming growth factor beta (TGF-beta) signaling, indicating that like Cripto, GRP78 inhibits this pathway. |
| GO:0042149 cellular response to glucose starvation | ISO GO_REF:0000121 | KEEP AS NON CORE | 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. Reason: Induction by glucose deprivation is the defining historical property of GRP78, and the human source (IDA, PMID:10085239) shows glucose-dependent repression of GRP78 mRNA. The term describes a change in BiP expression in response to the stimulus rather than BiP's own molecular role, so it is kept as a non-core response annotation rather than a core function. Supporting Evidence: PMID:10085239 Fructose, galactose, mannose, 2-deoxyglucose and xylitol were found to maintain the mRNA content of both AS and the glucose-regulated protein GRP78 in a state of repression |
| GO:0006983 ER overload response | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ISO from mouse Hspa5 for ER overload response. BiP is involved in managing ER stress including protein overload situations. Reason: GO:0006983 ER overload response is defined as signalling initiated by protein accumulation in the ER that leads to NF-kappaB-dependent transcription. The mouse source (IDA, PMID:11854325, a Chop knockout study in Akita mice) documents induction of Bip mRNA during misfolded-proinsulin stress, i.e. BiP as a readout of ER stress; it does not show BiP acting in NF-kappaB activation. BiP's actual roles in ER stress signalling are captured by GO:0030968, GO:0034976 and the IRE1/PERK regulation terms. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:95835 Β· mouse Hspa5 SUPPORTS SOURCE BUT NOT TARGET Sole ISO donor. The mouse annotation (IDA, PMID:11854325, acts_upstream_of_or_within) rests on induction of Bip mRNA in Akita mouse pancreas, which places BiP as an ER stress marker; transferring it to rat as GO:0006983, a term defined by NF-kappaB activation, conflates being induced by ER overload with acting in its signalling. Supporting Evidence: PMID:11854325 In the development of diabetes in Akita mice, mRNAs for the ER chaperone Bip and the ER stress-associated apoptosis factor Chop were induced in the pancreas. |
| GO:0043022 ribosome binding | ISO GO_REF:0000121 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:12065409 interacting with both the Sec61p complex and lumenal DnaK-like proteins, such as BiP. UniProtKB:P06761 May function as an allosteric modulator for SEC61 channel-forming translocon complex, likely cooperating with SEC62 to enable the productive insertion of these precursors into SEC61 channel |
| GO:0043025 neuronal cell body | IDA PMID:26088419 Activity-induced synaptic delivery of the GluN2A-containing ... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:26088419 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. |
| GO:0043198 dendritic shaft | IDA PMID:26088419 Activity-induced synaptic delivery of the GluN2A-containing ... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:26088419 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. |
| GO:0016020 membrane | IDA PMID:23444373 SDF2L1 interacts with the ER-associated degradation machiner... | MARK AS OVER ANNOTATED | Summary: IDA mapped to membrane localization from PMID:23444373, a study of SDF2L1/BiP/ERAD interactions in pancreatic beta-cells. The cited evidence demonstrates a BiP-SDF2L1-ERAD interaction, not membrane residency per se. Reason: BiP is a soluble ER-lumenal protein with no membrane-spanning domain; the generic "membrane" term is uninformative. The supporting study documents a BiP-ERAD machinery interaction rather than direct membrane localization. BiP's transient membrane association is better captured by the retained ER membrane (GO:0005789) annotation. Marked over-annotated for consistency with the IBA "membrane" annotation. Supporting Evidence: PMID:23444373 Immunoprecipitation and binding assays demonstrated that SDF2L1 interacts with the ER chaperone GRP78/BiP, the ER-associated degradation (ERAD) machinery and with misfolded proinsulin. |
| GO:0034976 response to endoplasmic reticulum stress | IDA PMID:23444373 SDF2L1 interacts with the ER-associated degradation machiner... | ACCEPT | 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. 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. Supporting Evidence: PMID:23444373 SDF2L1 protein levels are increased in response to ER stress-inducing compounds [...] SDF2L1 interacts with the ER chaperone GRP78/BiP |
| GO:0051787 misfolded protein binding | IDA PMID:23444373 SDF2L1 interacts with the ER-associated degradation machiner... | ACCEPT | 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. 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. Supporting Evidence: PMID:23444373 SDF2L1 interacts with the ER chaperone GRP78/BiP, the ER-associated degradation (ERAD) machinery and with misfolded proinsulin. |
| GO:0005790 smooth endoplasmic reticulum | IDA PMID:22665516 An interaction map of endoplasmic reticulum chaperones and f... | KEEP AS NON CORE | Summary: Curator IDA for smooth ER localization from PMID:22665516, the ER chaperone/foldase interaction map study. The cached abstract describes ER-lumenal chaperone/foldase interaction networks but does not itself detail the smooth-ER fractionation evidence behind this curated term. 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. Retained as the curated IDA assignment. Supporting Evidence: PMID:22665516 Using complementary ER-specific methods, we have mapped interactions between ER-lumenal chaperones and foldases |
| GO:0005783 endoplasmic reticulum | IDA PMID:19474315 UBXD4, a UBX-containing protein, regulates the cell surface ... | ACCEPT | Summary: Curator IDA for ER localization from PMID:19474315, a study of UBXD4 and nicotinic acetylcholine receptor trafficking. The cached abstract characterizes UBXD4 (ER/cis-Golgi) and does not directly detail the BiP localization evidence; ER is nonetheless the well-established primary compartment for BiP and is corroborated by multiple independent annotations below. Reason: ER localization is the primary and well-established compartment for BiP, supported by numerous independent annotations. Retained as the curated IDA assignment. Supporting Evidence: UniProtKB:P06761 SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0005783 endoplasmic reticulum | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from mouse/human Hspa5 for ER. An additional ISO entry for ER localization. Redundant with IDA above. Reason: ER is the primary organelle. Consistent with IDA and other evidence. Supporting Evidence: UniProtKB:P06761 SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | ISO GO_REF:0000121 | ACCEPT | Summary: Additional ISO entry from mouse Hspa5 for ER lumen. Redundant with IBA, IEA, and another ISO annotation. Reason: ER lumen is the primary location. This is a duplicate ISO entry from a different source. Supporting Evidence: UniProtKB:P06761 SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0051787 misfolded protein binding | ISO GO_REF:0000121 | ACCEPT | Summary: Additional ISO from mouse Hspa5. Redundant with IDA and IEA annotations for misfolded protein binding. Reason: Misfolded protein binding is a core function. This additional ISO is consistent with other evidence. Supporting Evidence: UniProtKB:P06761 Involved in the correct folding of proteins and degradation of misfolded proteins via its interaction with DNAJC10/ERdj5 |
| GO:0034663 endoplasmic reticulum chaperone complex | ISO GO_REF:0000121 | ACCEPT | Summary: Additional ISO from human HSPA5. Another duplicate for ER chaperone complex membership. Reason: ER chaperone complex membership is well established. This is a third entry (with IBA and another ISO) for the same term. Supporting Evidence: UniProtKB:P06761 Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29 |
| GO:0001554 luteolysis | IEP PMID:25332219 Endoplasmic reticulum stress-mediated apoptotic pathway is i... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:25332219 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 |
| GO:0051402 neuron apoptotic process | IEP PMID:9058202 Induction of Bip mRNA upon programmed cell death of differen... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:9058202 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 |
| GO:0071277 cellular response to calcium ion | IEP PMID:9058202 Induction of Bip mRNA upon programmed cell death of differen... | KEEP AS NON CORE | Summary: IEP for cellular response to calcium ion. PMID:9058202 showed that alterations of intracellular calcium homeostasis (A23187, BAPTA) induced BiP mRNA expression. 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. Supporting Evidence: PMID:9058202 Alterations of intracellular calcium homeostasis thus appear to induce Bip mRNA expression as well as apoptosis in PC12 (22a) cells. |
| GO:0071320 cellular response to cAMP | IEP PMID:9058202 Induction of Bip mRNA upon programmed cell death of differen... | KEEP AS NON CORE | Summary: IEP for cellular response to cAMP. PMID:9058202 showed cAMP suppressed BiP mRNA induction during NGF-deprivation-dependent neuronal cell death. 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. Supporting Evidence: PMID:9058202 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+. |
| GO:0010976 positive regulation of neuron projection development | IMP PMID:10936191 Facilitatory roles of novel compounds designed from cyclopen... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:10936191 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. |
| GO:0030182 neuron differentiation | IEP PMID:19322020 Induction of unfolded protein response during neuronal induc... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:19322020 BIP/GRP78 protein expression was time-dependently increased, and three branches of UPR were all activated. |
| GO:0034976 response to endoplasmic reticulum stress | IEP PMID:22189689 Thapsigargin down-regulates protein levels of GRP78/BiP in I... | ACCEPT | 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. 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. Supporting Evidence: PMID:22189689 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. |
| GO:1904313 response to methamphetamine hydrochloride | IEP PMID:19826936 Proteomic analysis reveals differentially expressed proteins... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:19826936 78 kDa glucose-regulated protein (GRP 78) |
| GO:1990090 cellular response to nerve growth factor stimulus | IEP PMID:10936191 Facilitatory roles of novel compounds designed from cyclopen... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:10936191 BiP/GRP78 protein level increased in response to NEPPs |
| GO:0042220 response to cocaine | IEP PMID:17849098 Cocaine increases immunoglobulin heavy chain binding protein... | KEEP AS NON CORE | 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. Reason: BiP induction by cocaine reflects drug-induced ER stress in striatal neurons. IEP expression correlation, not a direct function. Supporting Evidence: PMID:17849098 BiP and caspase-12 immunoreactivities were significantly increased |
| GO:0071466 cellular response to xenobiotic stimulus | IEP PMID:18757512 Effect of an inducer of BiP, a molecular chaperone, on endop... | KEEP AS NON CORE | Summary: IEP for cellular response to xenobiotic stimulus. PMID:18757512 studied BiP induction in retinal cells by an ER stress inducer, showing protective effects. Reason: BiP induction in response to xenobiotic stimuli reflects its role as an ER stress-responsive protein. IEP expression pattern. Supporting Evidence: PMID:18757512 BIX preferentially induced BiP mRNA expression both time- and concentration-dependently in RGC-5 cells. |
| GO:0071480 cellular response to gamma radiation | IEP PMID:20470193 ER stress induced by ionising radiation in IEC-6 cells. | KEEP AS NON CORE | Summary: IEP for cellular response to gamma radiation. PMID:20470193 found ER stress including BiP expression changes after ionising radiation in IEC-6 cells. Reason: BiP expression change after gamma radiation reflects radiation- induced ER stress. IEP expression correlation. Supporting Evidence: PMID:20470193 IR induced up-regulation of ER stress marker including BiP and GRP94 at protein and mRNA levels in IEC-6 cells. |
| GO:0097501 stress response to metal ion | IEP PMID:17915553 Activation profiles of HSPA5 during the glomerular mesangial... | KEEP AS NON CORE | 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. Reason: BiP activation by metal ion stress reflects ER stress induction. IEP expression pattern, not a direct metal-binding or metal- response function. Supporting Evidence: PMID:17915553 HSPA5 activation profiles in rat glomerular mesangial cells (rGMCs) challenged with heavy metals (HgCl2 or Pb2+ acetate) |
| GO:0071287 cellular response to manganese ion | IEP PMID:23934647 Ξ±-Synuclein is involved in manganese-induced ER stress via P... | KEEP AS NON CORE | 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. Reason: BiP induction by manganese reflects manganese-induced ER stress via the PERK pathway. IEP expression correlation. Supporting Evidence: PMID:23934647 there was a dose-dependent increase in the protein expression of 78, 94-kDa glucose-regulated protein (GRP78/94), C/EBP homologous protein (CHOP), and caspase-12. |
| GO:0071236 cellular response to antibiotic | IEP PMID:19332540 Palmitate induces insulin resistance in H4IIEC3 hepatocytes ... | KEEP AS NON CORE | 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. Reason: BiP expression change in response to antibiotic treatment likely reflects drug-induced ER stress. IEP expression pattern. Supporting Evidence: PMID:19332540 did not alter the expression level of GRP78 mRNA or the splicing pattern of XBP-1, unlike tunicamycin, an agent commonly used to induce ER stress |
| GO:0051082 unfolded protein binding | IPI PMID:11884402 Identification of ERp29, an endoplasmic reticulum lumenal pr... | MODIFY | 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. 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. GOA no longer carries this annotation (retired at the 2026 GOA refresh); the review is kept for provenance. GOA now carries GO:0044183 protein folding chaperone (IPI, same reference, with thyroglobulin RGD:3848) in its place, matching the recommended replacement. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:11884402 Preferential association with the urea-denatured Tg-Sepharose was indicative of either direct or circuitous ERp29/Tg interactions in a chaperone-like manner. |
| GO:0005789 endoplasmic reticulum membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Additional ISO from human HSPA5 for ER membrane. Duplicate ISO entry for ER membrane localization. Reason: ER membrane association is consistent with BiP's role at the translocon and with membrane-bound ERAD components. Supporting Evidence: UniProtKB:P06761 May function as an allosteric modulator for SEC61 channel-forming translocon complex, likely cooperating with SEC62 to enable the productive insertion of these precursors into SEC61 channel |
| GO:0005793 endoplasmic reticulum-Golgi intermediate compartment | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Additional ISO from human HSPA5. Duplicate entry for ERGIC. Reason: ERGIC is a transit compartment. Consistent with other ISO entry. Supporting Evidence: file:rat/Hspa5/Hspa5-deep-research-falcon.md BiP is primarily localized to the **ER lumen**, and ER retention depends on the **C-terminal KDEL** retrieval motif and KDEL receptor (KDELR)-mediated retrieval between ER and Golgi. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: IEA from InterPro (IPR013126, Hsp70 family) for ATP binding. BiP has an N-terminal nucleotide-binding domain whose ATP-bound state controls substrate binding and release. Reason: ATP binding is integral to the BiP chaperone cycle and is consistent with the ISO ATP binding row and the ATP hydrolysis annotations. Supporting Evidence: UniProtKB:P06761 in the ATP-bound state the two domains are tightly coupled, which results in drastically accelerated kinetics in both binding and release of polypeptide substrates |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO from human HSPA5 (P11021) for cytoplasm (located_in). Duplicate of the existing cytoplasm rows with a different donor. Reason: Consistent with the other cytoplasm rows: a minor, stress- or context-dependent pool outside the ER. UniProt lists cytoplasm by similarity to mouse Hspa5. Not a core location for a KDEL-retained lumenal chaperone. Supporting Evidence: UniProtKB:P06761 Cytoplasm {ECO:0000250|UniProtKB:P20029} |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Hspa5 (P20029) for cytoplasm (located_in). This is the UniProt-curated similarity assignment underlying the UniProt subcellular location line. Reason: Same judgment as the other cytoplasm rows; the mouse donor is the source UniProt cites for this location. Non-core relative to the ER lumen. Supporting Evidence: UniProtKB:P06761 Cytoplasm {ECO:0000250|UniProtKB:P20029} |
| GO:0005788 endoplasmic reticulum lumen | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from human HSPA5 (P11021) for endoplasmic reticulum lumen with the located_in qualifier (the existing ISO row from the same donor uses is_active_in). Reason: The ER lumen is the primary compartment of BiP, retained there by its C-terminal KDEL motif. Supporting Evidence: UniProtKB:P06761 SUBCELLULAR LOCATION: Endoplasmic reticulum lumen file:rat/Hspa5/Hspa5-deep-research-falcon.md BiP is primarily localized to the **ER lumen**, and ER retention depends on the **C-terminal KDEL** retrieval motif and KDEL receptor (KDELR)-mediated retrieval between ER and Golgi. |
| GO:0005788 endoplasmic reticulum lumen | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from human HSPA5 (P11021) for endoplasmic reticulum lumen; the UniProt similarity assignment behind the subcellular location line. Reason: The ER lumen is the primary compartment of BiP. Consistent with the IBA, IEA and ISO rows for the same term. Supporting Evidence: UniProtKB:P06761 SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0009725 response to hormone | IDA PMID:11884402 Identification of ERp29, an endoplasmic reticulum lumenal pr... | UNDECIDED | Summary: IDA for response to hormone from PMID:11884402, a study of ERp29 in the thyroglobulin folding complex in FRTL-5 rat thyrocytes treated with thyroid-stimulating hormone (TSH). Reason: The cached abstract states that ERp29 was induced by TSH; it does not say whether BiP levels changed. The curator presumably saw a BiP response to TSH in the full text, which is not available here, so the annotation can neither be confirmed nor rejected. An expression change in response to a hormone would in any case be a non-core response annotation (and IEP rather than IDA would be the usual evidence code). Supporting Evidence: PMID:11884402 ERp29 was induced upon treatment of FRTL-5 rat thyrocytes with the thyroid-stimulating hormone, which is essential for the maintenance of thyroid cells and Tg biosynthesis. |
| GO:0009986 cell surface | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO from human HSPA5 (P11021) for cell surface. Duplicate of the existing cell surface rows with the human donor. Reason: Cell-surface GRP78 is a documented non-canonical pool in epithelial and stressed or tumour cells; it is not the primary location. Supporting Evidence: UniProtKB:P06761 Localizes to the cell surface in epithelial cells; high levels of free iron promotes cell surface localization |
| GO:0042470 melanosome | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO from human HSPA5 (P11021) for melanosome, based on mass-spectrometry detection in melanosome fractions. Reason: Proteomic detection of an abundant secretory-pathway chaperone in melanosome fractions; consistent with the IEA melanosome row and kept as non-core. Supporting Evidence: UniProtKB:P06761 Identified by mass spectrometry in melanosome fractions from stage I to stage IV |
| GO:0042470 melanosome | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from human HSPA5 (P11021) for melanosome; the UniProt similarity assignment behind the subcellular location line. Reason: Same judgment as the other melanosome rows: proteomic detection, not a functional compartment for BiP. Supporting Evidence: UniProtKB:P06761 Identified by mass spectrometry in melanosome fractions from stage I to stage IV |
| GO:0044183 protein folding chaperone | IEA GO_REF:0000117 | ACCEPT | Summary: IEA (ARBA rule ARBA00029119) for protein folding chaperone. Reason: Protein folding chaperone is the core molecular function of BiP, consistent with the IBA, ISO and IPI rows for the same term. Supporting Evidence: UniProtKB:P06761 Endoplasmic reticulum chaperone that plays a key role in protein folding and quality control in the endoplasmic reticulum lumen UniProtKB:P06761 J domain-containing co-chaperones (DNAJB9/ERdj4 or DNAJC10/ERdj5) stimulate the ATPase activity and are required for efficient substrate recognition by HSPA5/BiP |
| GO:0044183 protein folding chaperone | IPI PMID:11884402 Identification of ERp29, an endoplasmic reticulum lumenal pr... | ACCEPT | Summary: IPI for protein folding chaperone from PMID:11884402, with thyroglobulin (RGD:3848) as the interacting client. GOA now uses this term in place of the retired GO:0051082 unfolded protein binding row from the same paper. Reason: The study places BiP in large ER chaperone complexes with the folding thyroglobulin client in rat thyrocytes, and thyroglobulin affinity chromatography co-isolates ER chaperones with a preference for denatured thyroglobulin. This is client binding in the course of folding, which GO:0044183 describes; it matches the replacement recommended in the retired row and the MODIFY for PMID:7916014. Supporting Evidence: PMID:11884402 Chemical cross-linking followed by the cell lysis and immunoprecipitation of ERp29 or Tg revealed association of these proteins and additionally, immunocomplexes that also included major ER chaperones, BiP and GRP94. PMID:11884402 Folding and post-translational modification of the thyroid hormone precursor, thyroglobulin (Tg), in the endoplasmic reticulum (ER) of the thyroid epithelial cells is facilitated by several molecular chaperones and folding enzymes, such as BiP, GRP94, calnexin, protein disulfide isomerase, ERp72, and others. |
| GO:0045732 positive regulation of protein catabolic process | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ISO from mouse Hspa5 (MGI:95835) for positive regulation of protein catabolic process. The mouse source is an IDA from PMID:18923430 (BHF-UCL), which studies BiP-driven release of misfolded substrates from the J-domain co-chaperone P58/DNAJC3. Reason: The source experiment shows that BiP and ATP dissociate P58 from its misfolded substrate (substrate handover), not that BiP increases protein catabolism; the paper reports no degradation readout for BiP and finds no effect of P58 on degradation of model substrates. BiP does contribute to degradation of misfolded ER proteins, but as a participant in ERAD, which is captured by GO:0036503 ERAD quality control pathway, rather than as a regulator of catabolism. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:95835 Β· mouse Hspa5 SOURCE BAD Sole ISO donor. The mouse annotation is IDA from PMID:18923430, whose full text describes BiP- and ATP-dependent release of misfolded substrates from P58/DNAJC3 and contains no BiP-dependent degradation assay, so the regulation-of-catabolism term overstates the source; the propagation path itself (mouse to rat BiP ortholog) is sound. Supporting Evidence: PMID:18923430 BiP-induced dissociation of P58 from its substrate depends on the presence of ATP and on interactions with P58's J-domain PMID:18923430 These negative results suggest that P58 does not have a pervasive role in clearing the ER of misfolded proteins by promoting their degradation. UniProtKB:P06761 Involved in the correct folding of proteins and degradation of misfolded proteins via its interaction with DNAJC10/ERdj5 |
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