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

Identity

HGNC
LOCATION
9q33.3
LOCUSID
ALIAS
BIP,GRP78,HEL-S-89n
FUSION GENES

DNA/RNA

Atlas Image

Description

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

Transcription

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).

Pseudogene

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

Proteins

Note

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).

Description

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).

Expression

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.

Localisation

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.

Function

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.

Homology

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.

Mutations

Germinal

Not known.

Somatic

Not known.

Implicated in

Entity name
Various cancers such as astrocytoma, breast cancer, glioblastoma, liver cancer, lung cancer, and prostate cancer
Note
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.
Disease
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)
Note
HspA5/BiP has been linked to a group of infectious diseases that are caused by Shigella toxin producing E. coli (such as HUS).
Disease
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)
Note
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.

Article Bibliography

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

Variants:

dbSNP: 3309
ClinVar: 3309
TCGA: ENSG00000044574
COSMIC: HSPA5

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000044574ENST00000324460P11021
ENSG00000044574ENST00000324460V9HWB4

Expression (GTEx)

0
100
200
300
400
500
600
700
800

Pathways

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
HemostasisREACTOMER-HSA-109582
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
Low
Medium
High

PharmGKB

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

References

Pubmed IDYearTitleCitations
372863652024Structural basis for the mechanism of interaction of SARS-CoV-2 B.1.640.2 variant RBD with the host receptors hACE2 and GRP78.0
378989942024lncRNA HOTAIRM1 Activated by HOXA4 Drives HUVEC Proliferation Through Direct Interaction with Protein Partner HSPA5.0
380851072024GRP78 promotes bone metastasis of prostate cancer by regulating bone microenvironment through Sonic hedgehog signaling.1
382722072024GRP78 Downregulation in Keratinocytes Promotes Skin Inflammation through the Recruitment and Activation of CCR6(+) IL-17A-Producing γδ T Cells.1
384229122024Prediction of the binding location between the nuclear inhibitor of DNA binding and differentiation 2 (ID2) and HSPA5.0
386134622024SARS-CoV-2 Spike Protein-Derived Cyclic Peptides as Modulators of Spike Interaction with GRP78.0
387107922024The interaction of GRP78 and Zika virus E and NS1 proteins occurs in a chaperone-client manner.0
387248122024Association between Polymorphisms of Heat Shock Protein HSPA5 and Risk of Type 2 Diabetes Mellitus.0
387268202024A study on expression of GRP78 and CHOP in neutrophil endoplasmic reticulum and their relationship with neutrophil apoptosis in the development of sepsis.0
387754802024GRP78 recognizes EV-F 3D protein and activates NF-κB to repress virus replication by interacting with CHUK/IKBKB.0
372863652024Structural basis for the mechanism of interaction of SARS-CoV-2 B.1.640.2 variant RBD with the host receptors hACE2 and GRP78.0
378989942024lncRNA HOTAIRM1 Activated by HOXA4 Drives HUVEC Proliferation Through Direct Interaction with Protein Partner HSPA5.0
380851072024GRP78 promotes bone metastasis of prostate cancer by regulating bone microenvironment through Sonic hedgehog signaling.1
382722072024GRP78 Downregulation in Keratinocytes Promotes Skin Inflammation through the Recruitment and Activation of CCR6(+) IL-17A-Producing γδ T Cells.1
384229122024Prediction of the binding location between the nuclear inhibitor of DNA binding and differentiation 2 (ID2) and HSPA5.0

Citation

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/case-report-explorer/js/hgnc