Endoplasmic reticulum chaperone BiP (HSPA5)
The protein contains 654 amino acids for an estimated molecular weight of 72333 Da.
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 ERN1/IRE1-mediated unfolded protein response (UPR) (PubMed:1550958, PubMed:19538957). 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). Accumulation of misfolded protein in the endoplasmic reticulum causes release of HSPA5/BiP from ERN1/IRE1, allowing homodimerization and subsequent activation of ERN1/IRE1 (By similarity). 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).', '(Microbial infection) Plays an important role in viral (updated: June 2, 2021)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology.
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| Variant | Description |
|---|---|
| dbSNP:rs35356639 |
Biological Process
ATF6-mediated unfolded protein response
Blood coagulation
Cellular protein metabolic process
Cellular response to antibiotic
Cellular response to calcium ion
Cellular response to cAMP
Cellular response to drug
Cellular response to gamma radiation
Cellular response to glucose starvation
Cellular response to heat
Cellular response to interleukin-4
Cellular response to manganese ion
Cellular response to nerve growth factor stimulus
Cellular response to unfolded protein
Cerebellar Purkinje cell layer development
Cerebellum structural organization
Chaperone cofactor-dependent protein refolding
Endoplasmic reticulum unfolded protein response
ER overload response
IRE1-mediated unfolded protein response
Luteolysis
Maintenance of protein localization in endoplasmic reticulum
Negative regulation of apoptotic process
Negative regulation of IRE1-mediated unfolded protein response
Negative regulation of protein homodimerization activity
Negative regulation of protein-containing complex assembly
Negative regulation of transforming growth factor beta receptor signaling pathway
Neuron apoptotic process
Neuron differentiation
Obsolete activation of signaling protein activity involved in unfolded protein response
PERK-mediated unfolded protein response
Platelet activation
Platelet degranulation
Positive regulation of cell migration
Positive regulation of neuron projection development
Positive regulation of protein ubiquitination
Positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress
Posttranslational protein targeting to membrane, translocation
Protein folding in endoplasmic reticulum
Protein refolding
Regulation of ATF6-mediated unfolded protein response
Regulation of IRE1-mediated unfolded protein response
Regulation of PERK-mediated unfolded protein response
Regulation of protein folding in endoplasmic reticulum
Response to cocaine
Response to methamphetamine hydrochloride
Response to unfolded protein
Stress response to metal ion
Substantia nigra development
Toxin transport
Ubiquitin-dependent ERAD pathway
Cellular Component
Cell surface
Cytoplasm
Cytosol
Endoplasmic reticulum
Endoplasmic reticulum chaperone complex
Endoplasmic reticulum lumen
Endoplasmic reticulum membrane
Endoplasmic reticulum-Golgi intermediate compartment
Extracellular exosome
Extracellular matrix
Focal adhesion
Integral component of endoplasmic reticulum membrane
Intracellular membrane-bounded organelle
Melanosome
Membrane
Midbody
Mitochondrion
Myelin sheath
Nucleus
Plasma membrane
Protein complex
Protein-containing complex
Smooth endoplasmic reticulum
Molecular Function
ATP binding
ATPase
ATPase activity, coupled
Cadherin binding
Calcium ion binding
Chaperone binding
Enzyme binding
Glycoprotein binding
Heat shock protein binding
Misfolded protein binding
Protein domain specific binding
Protein folding chaperone
Ribosome binding
Ubiquitin protein ligase binding
Unfolded protein binding
The reference OMIM entry for this protein is 138120
Heat-shock 70-kd protein 5; hspa5
Glucose-regulated protein, 78-kd; grp78
Immunoglobulin heavy chain-binding protein; bip
DESCRIPTION
When Chinese hamster K12 cells are starved of glucose, the synthesis of several proteins, called glucose-regulated proteins (GRPs), is markedly increased. Hendershot et al. (1994) pointed out that one of these, GRP78 (HSPA5), also referred to as 'immunoglobulin heavy chain-binding protein' (BiP), is a member of the heat-shock protein-70 (HSP70) family and is involved in the folding and assembly of proteins in the endoplasmic reticulum (ER). Because so many ER proteins interact transiently with GRP78, it may play a key role in monitoring protein transport through the cell.CLONING
Lee et al. (1981) cloned the hamster Grp78 gene. Ting and Lee (1988) isolated and characterized the human GRP78 gene. GRP78 is highly conserved in evolution and is transcriptionally regulated (Lee et al., 1983; Ting and Lee, 1988).GENE FUNCTION
To examine how the binding of BiP influences the conformational maturation of thyroglobulin (TG; 188450), Muresan and Arvan (1998) expressed TG in Chinese hamster ovary (CHO) cells genetically manipulated for selectively increased BiP expression (CHO-B cells). The TG expressed in CHO-B cells did not contain any mutations that induce misfolding (i.e., no unfolded protein response), so that levels of all other ER chaperones were normal. Increased availability of BiP did not accelerate TG secretion; rather, the export of newly synthesized TG was delayed. TG that was detained intracellularly was concentrated in the ER. Muresan and Arvan (1998) concluded that increased binding of BiP to TG leads to its delayed conformational maturation in the ER. Shen et al. (2002) found that HSPA5 binds ATF6 (605537) and dissociates from it in response to ER stress. They showed that deletion of luminal HSPA5 binding sites from ATF6, while retaining a Golgi localization signal, resulted in constitutive translocation of ATF6 to the Golgi. In cells overexpressing HSPA5, they observed that translocation of ATF6 to the Golgi was slowed. Shen et al. (2002) concluded that HSPA5 retains ATF6 in the ER by inhibiting its Golgi localization signals and that dissociation of HSPA5 during ER stress allows ATF6 to be transported to the Golgi. Sommer and Jarosch (2002) summarized the findings of Shen et al. (2002) in a discussion of the proteins involved in regulating levels of aberrant proteins within the ER. They suggested that the findings of Shen et al. (2002) demonstrated that HSPA5 is a key element in sensing the folding capacity within the ER. Two members of the HSP70 family are required for protein biogenesis in the yeast endoplasmic reticulum: Lhs1 (homologous to HYOU1; 601746) and Kar2 (homologous to HSPA5). Steel et al. (2004) found that Lhs1 and Kar2 specifically interacted to couple, and coordinately regulate, their respective activities. Lhs1 stimulated Kar2 by providing a specific nucleotide exchange activity, whereas Kar2 reciprocally activated the Lhs1 ATPase. In yeast, the 2 ATPase activities are coupled, and their coordinated regulation is essential for normal function in vivo. Ushioda et al. (2008) found that the ER-resident protein ERDJ5 (607987) had a reductase activity, cleaved the disulfide bonds of misfolded proteins, and accelerated ER-associated degradation (ERAD) through its physical and functional associations with EDEM (607673) and the ER-resident chaperone BIP. Thus, Ushioda et al. (2008) concluded that ERDJ5 is a member of a supramolecular ERAD complex that recognizes and unfolds ... More on the omim web site
July 1, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.
June 29, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.
Nov. 16, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
April 12, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 5, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
June 20, 2017: Protein entry updated
Automatic update: comparative model was added.
March 15, 2016: Protein entry updated
Automatic update: OMIM entry 138120 was added.
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed