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Details on Person UniProt:P11021 HSPA5
| Class:Id | ReferenceGeneProduct:55906 |
|---|---|
| _chainChangeLog | signal peptide:1-18 added on Fri February 6 2015;chain:19-654 added on Fri February 6 2015 |
| _displayName | UniProt:P11021 HSPA5 |
| _timestamp | 2025-08-15 21:59:04 |
| chain | signal peptide:1-18 chain:19-654 |
| checksum | 59B7D8D85BC32A00 |
| comment | FUNCTION Endoplasmic reticulum chaperone that plays a key role in protein folding and quality control in the endoplasmic reticulum lumen (PubMed:2294010, PubMed:23769672, PubMed:23990668, PubMed:28332555). Involved in the correct folding of proteins and degradation of misfolded proteins via its interaction with DNAJC10/ERdj5, probably to facilitate the release of DNAJC10/ERdj5 from its substrate (By similarity). Acts as a key repressor of the EIF2AK3/PERK and ERN1/IRE1-mediated unfolded protein response (UPR) (PubMed:11907036, PubMed:1550958, PubMed:19538957, PubMed:36739529). 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 (By similarity). Also binds and inactivates EIF2AK3/PERK in unstressed cells (PubMed:11907036). Accumulation of misfolded protein in the endoplasmic reticulum causes release of HSPA5/BiP from ERN1/IRE1 and EIF2AK3/PERK, allowing their homodimerization and subsequent activation (PubMed:11907036). Plays an auxiliary role in post-translational transport of small presecretory proteins across endoplasmic reticulum (ER). 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. Appears to specifically regulate translocation of precursors having inhibitory residues in their mature region that weaken channel gating. May also play a role in apoptosis and cell proliferation (PubMed:26045166).FUNCTION (Microbial infection) Plays an important role in viral binding to the host cell membrane and entry for several flaviruses such as Dengue virus, Zika virus and Japanese encephalitis virus (PubMed:15098107, PubMed:28053106, PubMed:33432092). Acts as a component of the cellular receptor for Dengue virus serotype 2/DENV-2 on human liver cells (PubMed:15098107).FUNCTION (Microbial infection) Acts as a receptor for CotH proteins expressed by fungi of the order mucorales, the causative agent of mucormycosis, which plays an important role in epithelial cell invasion by the fungi (PubMed:20484814, PubMed:24355926, PubMed:32487760). Acts as a receptor for R.delemar CotH3 in nasal epithelial cells, which may be an early step in rhinoorbital/cerebral mucormycosis (RCM) disease progression (PubMed:32487760).CATALYTIC ACTIVITY ATP + H2O = ADP + phosphate + H(+)ACTIVITY REGULATION The chaperone activity is regulated by ATP-induced allosteric coupling of the nucleotide-binding (NBD) and substrate-binding (SBD) domains. In the ADP-bound and nucleotide-free (apo) states, the two domains have little interaction (PubMed:26655470). In contrast, 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 (PubMed:26655470). J domain-containing co-chaperones (DNAJB9/ERdj4 or DNAJC10/ERdj5) stimulate the ATPase activity and are required for efficient substrate recognition by HSPA5/BiP (By similarity). Homooligomerization inactivates participating HSPA5/BiP protomers and probably act as reservoirs to store HSPA5/BiP molecules when they are not needed by the cell (By similarity).SUBUNIT Monomer and homooligomer; homooligomerization via the interdomain linker inactivates the chaperone activity and acts as a storage of HSPA5/BiP molecules (By similarity). Interacts with DNAJC1 (via J domain) (By similarity). Component of an EIF2 complex at least composed of CELF1/CUGBP1, CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5 (By similarity). Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX (By similarity). Interacts with TMEM132A and TRIM21 (PubMed:12699405). May form a complex with ERLEC1, OS9, SEL1L and SYVN1 (PubMed:18264092, PubMed:18502753). Interacts with DNAJC10 (PubMed:12411443, PubMed:23769672). Interacts with DNAJB9/ERdj4; leading to recruit HSPA5/BiP to ERN1/IRE1 (By similarity). Interacts with ERN1/IRE1 (via luminal domain); the interaction takes place following interaction with DNAJB9/ERdj4 and leads to inactivate ERN1/IRE1, the interaction also competitively inhibits ERN1 interaction with MANF (PubMed:36739529). Interacts directly with MANF (via SAP domain); the interaction inhibits ATP binding to HSPA5/BiP and subsequent nucleotide exchange (By similarity). Interacts with EIF2AK3/PERK (via luminal domain); interaction leads to inactivate EIF2AK3/PERK (PubMed:11907036, PubMed:36739529). Interacts with MX1 (By similarity). Interacts with METTL23 (PubMed:23349634). Interacts with CEMIP; the interaction induces calcium leakage from the endoplasmic reticulum and cell migration (PubMed:23990668). Interacts with PCSK4 form; the interaction takes place in the endoplasmic reticulum (PubMed:21080038). Interacts with CIPC (PubMed:26657846). Interacts with CCDC88B (via C-terminus); the interaction opposes ERN1-mediated JNK activation, protecting against apoptosis (PubMed:21289099). Interacts with INPP5K; necessary for INPP5K localization at the endoplasmic reticulum (PubMed:26940976). Interacts with MANF; the interaction is direct (PubMed:22637475). Interacts with LOXL2; leading to activate the ERN1/IRE1-XBP1 pathway of the unfolded protein response (PubMed:28332555). Interacts with CLU under stressed condition; interaction increases CLU protein stability; facilitates its retrotranslocation and redistribution to the mitochondria; cooperatively suppress stress-induced apoptosis by stabilizing mitochondrial membrane integrity (PubMed:22689054). Interacts with CCDC47 (By similarity). Interacts with CLN3 (Probable). Interacts with ELAPOR1; may regulate the function of HSPA5 in apoptosis and cell proliferation (PubMed:26045166). Interacts with CASP7 (PubMed:26045166). Interacts with ILDR2; the interaction stabilizes ILDR2 expression (By similarity). Interacts with ADAM7 (By similarity).SUBUNIT (Microbial infection) Interacts with Japanese encephalitis virus envelope protein E.SUBUNIT (Microbial infection) Interacts with R.delemar invasin CotH3 on the surface of nasal epithelial cells (PubMed:24355926, PubMed:32487760). Interacts with R.delemar invasin CotH2 (PubMed:24355926).SUBUNIT (Microbial infection) Interacts with Zika virus envelope protein E and non-structural protein 1 in a chaperone-client manner.INTERACTION Identified by mass spectrometry in melanosome fractions from stage I to stage IV (PubMed:12643545). Localizes to the cell surface of epithelial cells in response to high levels of free iron (PubMed:20484814, PubMed:24355926, PubMed:27159390).INDUCTION By endoplasmic reticulum stress (PubMed:21289099, PubMed:36739529). Induced in nasal epithelial cells by high free iron levels (PubMed:20484814, PubMed:27159390, PubMed:32487760). Induced in nasal epithelial cells in high glucose (PubMed:20484814, PubMed:27159390, PubMed:32487760). Induced in nasal epithelial cells by 3-hydroxybutyric acid (BHB) (PubMed:27159390, PubMed:32487760).DOMAIN The interdomain linker regulates the chaperone activity by mediating the formation of homooligomers. Homooligomers are formed by engagement of the interdomain linker of one HSPA5/BiP molecule as a typical substrate of an adjacent HSPA5/BiP molecule. HSPA5/BiP oligomerization inactivates participating HSPA5/BiP protomers. HSPA5/BiP oligomers probably act as reservoirs to store HSPA5/BiP molecules when they are not needed by the cell. When the levels of unfolded proteins rise, cells can rapidly break up these oligomers to make active monomers.PTM AMPylated by FICD (PubMed:25601083). In unstressed cells, AMPylation at Thr-518 by FICD inactivates the chaperome activity: AMPylated form is locked in a relatively inert state and only weakly stimulated by J domain-containing proteins (By similarity). In response to endoplasmic reticulum stress, de-AMPylation by the same protein, FICD, restores the chaperone activity (By similarity).DISEASE Autoantigen in rheumatoid arthritis.BIOTECHNOLOGY Antibodies against the protein protects endothelial cells from invasion by the fungus R.delemar, a causative agent of mucormycosis, and could thus potentially be used to treat mucormycosis disease (PubMed:20484814). Antibodies against the protein also protect a diabetic ketoacidosis mouse model against mucormycosis (PubMed:20484814).SIMILARITY Belongs to the heat shock protein 70 family.CAUTION AMPylation was initially reported to take place at Ser-365 and Thr-366 in vitro, and promote activation of HSPA5/BiP (PubMed:25601083). However, it was later shown that AMPylation takes place at Thr-518 and leads to inactivation of HSPA5/BiP. |
| description | recommendedName: fullName evidence="48"Endoplasmic reticulum chaperone BiP ecNumber evidence="31"3.6.4.10 alternativeName: fullName evidence="46"78 kDa glucose-regulated protein shortName evidence="46"GRP-78 alternativeName: fullName evidence="47"Binding-immunoglobulin protein shortName evidence="47"BiP alternativeName: fullName evidence="48"Heat shock protein 70 family protein 5 shortName evidence="48"HSP70 family protein 5 alternativeName: fullName evidence="50"Heat shock protein family A member 5 alternativeName: fullName evidence="47"Immunoglobulin heavy chain-binding protein |
| geneName | HSPA5 GRP78 |
| identifier | P11021 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Acetylation ATP-binding Chaperone Cytoplasm Direct protein sequencing Endoplasmic reticulum Host-virus interaction Hydrolase Isopeptide bond Methylation Nitration Nucleotide-binding Phosphoprotein Proteomics identification Reference proteome Signal Ubl conjugation |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9841277] Weiser, Joel [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21 [InstanceEdit:9948485] Weiser, Joel, 2025-05-21 [InstanceEdit:9963647] Weiser, Joel, 2025-08-15 |
| name | HSPA5 |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:5642283] ENSEMBL:ENSG00000044574 HSPA5 [Homo sapiens] |
| secondaryIdentifier | BIP_HUMAN B0QZ61 Q2EF78 Q9NPF1 Q9UK02 |
| sequenceLength | 654 |
| species | [Species:48887] Homo sapiens |
| (referenceEntity) | [EntityWithAccessionedSequence:351315] HSPA5 [endoplasmic reticulum membrane] [Homo sapiens] [EntityWithAccessionedSequence:351322] HSPA5 [extracellular region] [Homo sapiens] [EntityWithAccessionedSequence:387190] HSPA5 [endoplasmic reticulum lumen] [Homo sapiens] [EntityWithAccessionedSequence:985498] HSPA5 [lumenal side of endoplasmic reticulum membrane] [Homo sapiens] [EntityWithAccessionedSequence:5252042] HSPA5 [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:5252115] HSPA5 [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:9922467] HSPA5 [plasma membrane] [Homo sapiens] |
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No pathways have been reviewed or authored by UniProt:P11021 HSPA5 (55906)
