HSPA5 (heat shock 70kDa protein 5 (glucose-regulated protein, 78kDa))

2009-12-01   Richard Zimmermann , Johanna Dudek 

Medical Biochemistry, Molecular Biology, Saarland University, 66421 Homburg, Germany




Atlas Image


Starts at 127036953 bp and ends at 127043430 bp from pter.


The gene is constitutively expressed in all nucleated cells. Under cellular stress conditions (such as hypoxia or glucose starvation) transcritption is upregulated via the "unfolded protein response" (UPR).


Four pseudogenes were reported (human pseudogenes from protein P11021).



HspA5 (heat shock protein A5), also termed immunoglobulin heavy chain binding protein (BiP) or glucose regulated protein with an apparent mass of 78 kDa (Grp78) is a Hsp70-type molecular chaperone of the endoplasmic reticulum (ER).


The protein is synthesized as a precursor with an aminoterminal signal peptide of 18 amino acid residues that directs the precursor into the ER. The mature protein (i.e. after removal of the signal peptide by signal peptidase in the ER) contains 635 amino acid residues, including a carboxyterminal ER retention motif that comprises four amino acid residues (KDEL).


The HSPA5 gene is expressed in all nucleated cells, in particular in thyroid-, lung-, smooth muscle-, liver-, and various cells of the immune system. Under cellular stress conditions the gene is over-expressed due to UPR.
Atlas Image
Central role of HspA5/BiP in gene expression and calcium homeostasis. Typically, BiP is involved in protein transport into and in protein folding and assembly in the ER. Upon protein misfolding -either due to mutation in a client protein or to environmental conditions, such as hypoxia or glucose starvation- one or more proteins start to aggregate and therefore, sequester BiP. This removes BiP from its normal tasks as well as from the signaling molecules in the ER membrane (ATF6, IRE1, PERK). Subsequently, the unfolded protein response/UPR is activated and leads to a reduction of global protein synthesis and the over-production of ER chaperones and ERAD components (ERAD, ER associated protein degradation). If this response fails apoptosis is induced.


HspA5/BiP is a resident protein of the endoplasmic reticulum (ER). Typically, it is a soluble protein of the lumen of the ER. However, a subfraction of HspA5/BiP can be found on the cell surface of certain cell types, in particular of cancer cells.
Atlas Image
Interactome of HspA5/BiP. Calcium binding proteins are labeled with red asterisk, membrane proteins are shown in green. ERj, ER protein with j-domain; PDI, protein disulfide isomerase; Grp, glucose regulated protein.


The ER is involved in a variety of essential and interconnected processes, including protein biogenesis (protein transport into the ER, protein folding and assembly, and ER associated protein degradation), signal transduction (unfolded protein response/UPR), and calcium homeostasis. The central player in all these processes is the molecular chaperone HspA5/BiP. HspA5/BiP crucially depends on a number of interaction partners, including co-chaperones (ERj1 through ERj7), nucleotide exchange factors (Sil1, Grp170), other chaperones (calnexin, calreticulin, Grp94, UGGT), folding catalysts (protein disulfide isomerases/PDI, and peptidyl prolyl cis/trans isomerases such as Cyclophilin B) and signaling molecules (IRE1, ATF6, PERK, Sigma-1 receptor).
As a typical Hsp70, HspA5/BiP comprises an aminoterminal nucleotide binding domain and a carboxyterminal substrate (poly)peptide binding domain. Its functional cycle involves an ATP-form with low affinity for substrate (poly)peptides and an ADP-form with high substrate affinity and is regulated by Hsp40-type co-chaperones and nucleotide exchange factors.
Molecular chaperones of the Hsp70 type family reversibly bind to substrate polypeptides via the substrate binding domain (SBD). Typically, Hsp70 substrates are hydrophobic oligopeptides within more or less unfolded polypeptides. The binding of a substrate to the SBD inhibits unproductive interactions of the polypeptide and favors productive folding and assembly that occur concomitant with release from Hsp70. In addition, Hsp70s can regulate the activities of folded polypeptides.
Atlas Image
Functional cycle of BiP. An unfolded substrate (poly)peptide is shown in red. ADP, adenosine diphosphate; ATP, adenosine triphosphate; NBD, nucleotide binding domain; NEF, nucleotide exchange factor; Pi, inorganic phosphate; SBD, substrate binding domain with lid.


HspA5/BiP belongs to the heat shock protein 70 (Hsp70) family of molecular chaperones. As such it is structurally related to the cytosolic Hsp70s (Hsc70, Hsp70.1, Hsp70.3, Hsp70L1) and the mitochondrial Hsp70 (Grp75/mtHsp75). In addition, HspA5/BiP is structurally related to its nucleotide exchange factor Grp170 that also belongs to the Hsp70 protein family.



Not known.


Not known.

Implicated in

Entity name
Various cancers such as astrocytoma, breast cancer, glioblastoma, liver cancer, lung cancer, and prostate cancer
HspA5/BiP has been linked to various cancers. Due to poor vascularization and the resulting hypoxia and glucose starvation, tumor cells are prone to ER stress and therefore, UPR. In cultured cells, HspA5/BiP is one of the proteins involved in protecting cancer cells against ER stress-induced apoptosis.
HSPA5/BIP expression is highly upregulated in a variety of cancer tissues due to UPR. The HspA5/BiP protects cancer cells against apoptosis through various mechanisms : i) it fights protein aggegation in the ER, ii) due to its ability to bind Ca2+ it prevents calcium signaling in the cytosol, iii) it prevents the activation of pro-apoptotic components, such as BIK, BAX, pro-caspase 7 and pro-caspase 12. Furthermore, HspA5/BiP protects cancer cells against various chemotherapeutic agents that target the same pro-apoptotic components.
Entity name
Haemolytic uraemic syndrome (HUS)
HspA5/BiP has been linked to a group of infectious diseases that are caused by Shigella toxin producing E. coli (such as HUS).
Shiga toxigenic Escherichia coli (STEC) strains cause morbidity and mortality. Some of these pathogens produce Shiga toxin and AB5 toxin and are responsible for gastrointestinal diseases, such as HUS. During an infection, the bacterial cytotoxin enters human cells by endocytosis and retrograde transport to the ER. In the ER, BiP is the major target of the catalytic A-subunit, which inactivates BiP by limited proteolysis. Finally, all BiP functions are completely lost, and the affected cells die.
Entity name
Marinesco-Sjogren syndrome (MSS)
HspA5/BiP has indirectly been linked to a hereditary disease that is caused by a lack of function of the nucleotide exchange factor of BiP, termed Sil1.


Pubmed IDLast YearTitleAuthors
153805182004Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands.Arap MA et al
176816352007Visiting the ER: the endoplasmic reticulum as a target for therapeutics in traffic related diseases.Aridor M et al
30844971986Posttranslational association of immunoglobulin heavy chain binding protein with nascent heavy chains in nonsecreting and secreting hybridomas.Bole DG et al
180830962007Calcium signaling.Clapham DE et al
191519222009Functions and pathologies of BiP and its interaction partners.Dudek J et al
174400862007GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis.Fu Y et al
64175461983Immunoglobulin heavy chain binding protein.Haas IG et al
118070912002A new role for BiP: closing the aqueous translocon pore during protein integration into the ER membrane.Haigh NG et al
15633551992Interaction of BiP with newly synthesized immunoglobulin light chain molecules: cycles of sequential binding and release.Knittler MR et al
171272652007Molecular chaperones: multiple functions, pathologies, and potential applications.Macario AJ et al
174816122007ER chaperones in mammalian development and human diseases.Ni M et al
170240872006AB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP.Paton AW et al
162125022005Endoplasmic reticulum-associated degradation.Römisch K et al
127044262003Polypeptide-binding proteins mediate completion of co-translational protein translocation into the mammalian endoplasmic reticulum.Tyedmers J et al
150708902004Signaling the unfolded protein response from the endoplasmic reticulum.Zhang K et al

Other Information

Locus ID:

NCBI: 3309
MIM: 138120
HGNC: 5238
Ensembl: ENSG00000044574


dbSNP: 3309
ClinVar: 3309
TCGA: ENSG00000044574


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Protein exportKEGGko03060
Antigen processing and presentationKEGGko04612
Protein exportKEGGhsa03060
Antigen processing and presentationKEGGhsa04612
Prion diseasesKEGGko05020
Prion diseasesKEGGhsa05020
Protein processing in endoplasmic reticulumKEGGko04141
Protein processing in endoplasmic reticulumKEGGhsa04141
Thyroid hormone synthesisKEGGhsa04918
Thyroid hormone synthesisKEGGko04918
Metabolism of proteinsREACTOMER-HSA-392499
Unfolded Protein Response (UPR)REACTOMER-HSA-381119
ATF6 (ATF6-alpha) activates chaperonesREACTOMER-HSA-381033
ATF6 (ATF6-alpha) activates chaperone genesREACTOMER-HSA-381183
IRE1alpha activates chaperonesREACTOMER-HSA-381070
PERK regulates gene expressionREACTOMER-HSA-381042
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Class I MHC mediated antigen processing & presentationREACTOMER-HSA-983169
Antigen Presentation: Folding, assembly and peptide loading of class I MHCREACTOMER-HSA-983170
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
Response to elevated platelet cytosolic Ca2+REACTOMER-HSA-76005
Platelet degranulationREACTOMER-HSA-114608
Cellular responses to stressREACTOMER-HSA-2262752
Cellular response to heat stressREACTOMER-HSA-3371556
Regulation of HSF1-mediated heat shock responseREACTOMER-HSA-3371453

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA164713176Platinum compoundsChemicalClinicalAnnotationassociatedPD21940774
PA443622Carcinoma, Non-Small-Cell LungDiseaseClinicalAnnotationassociatedPD21940774


Pubmed IDYearTitleCitations
126655082003Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation.218
164721122006Stress induction of GRP78/BiP and its role in cancer.209
127138712003Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis.151
179069602007The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients.128
120975572002Hepatitis C virus subgenomic replicons induce endoplasmic reticulum stress activating an intracellular signaling pathway.121
202080722010Cell surface relocalization of the endoplasmic reticulum chaperone and unfolded protein response regulator GRP78/BiP.117
169121562006GRP78 as a novel predictor of responsiveness to chemotherapy in breast cancer.94
165432322006Activation and cross-talk between Akt, NF-kappaB, and unfolded protein response signaling in 1-LN prostate cancer cells consequent to ligation of cell surface-associated GRP78.90
156574212005Stable binding of ATF6 to BiP in the endoplasmic reticulum stress response.83
176407132007Glucose-regulated protein GRP78 is up-regulated in prostate cancer and correlates with recurrence and survival.78


Richard Zimmermann ; Johanna Dudek

HSPA5 (heat shock 70kDa protein 5 (glucose-regulated protein, 78kDa))

Atlas Genet Cytogenet Oncol Haematol. 2009-12-01

Online version: http://atlasgeneticsoncology.org/gene/40876/hspa5-(heat-shock-70kda-protein-5-(glucose-regulated-protein-78kda))