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Protein

Endoplasmic reticulum chaperone BiP

Gene

HSPA5

Organism
Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Endoplasmic reticulum chaperone that plays a key role in protein folding and quality control in the endoplasmic reticulum lumen (By similarity). 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:29198525). 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 (PubMed:29198525). Accumulation of misfolded protein in the endoplasmic reticulum causes release of HSPA5/BiP from ERN1/IRE1, allowing homodimerization and subsequent activation of ERN1/IRE1 (PubMed:29198525). 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.By similarity1 Publication

Catalytic activityi

ATP + H2O = ADP + phosphate.1 Publication

Activity regulationi

The chaperone activity is regulated by ATP-induced allosteric coupling of the nucleotide-binding (NBD) and substrate-binding (SBD) domains (By similarity). In the ADP-bound and nucleotide-free (apo) states, the two domains have little interaction (By similarity). 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 (By similarity). J domain-containing co-chaperones (DNAJB9/ERdj4 or DNAJC10/ERdj5) stimulate the ATPase activity and are required for efficient substrate recognition by HSPA5/BiP (PubMed:29064368). Homooligomerization inactivates participating HSPA5/BiP protomers and probably act as reservoirs to store HSPA5/BiP molecules when they are not needed by the cell (PubMed:26473973).By similarity2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei96ATPBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi36 – 39ATP1 PublicationImported4
Nucleotide bindingi227 – 229ATP1 PublicationImported3
Nucleotide bindingi293 – 300ATP1 PublicationImported8
Nucleotide bindingi364 – 367ATP1 PublicationImported4

GO - Molecular functioni

  • ATPase activity Source: UniProtKB
  • ATP binding Source: UniProtKB

GO - Biological processi

Keywordsi

Molecular functionChaperone, Hydrolase
LigandATP-binding, Nucleotide-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Endoplasmic reticulum chaperone BiPBy similarity (EC:3.6.4.101 Publication)
Alternative name(s):
78 kDa glucose-regulated proteinBy similarity
Short name:
GRP-78By similarity
Binding-immunoglobulin protein1 Publication
Short name:
BiP1 Publication
Heat shock protein 70 family protein 5By similarity
Short name:
HSP70 family protein 5By similarity
Heat shock protein family A member 5By similarity
Immunoglobulin heavy chain-binding protein1 Publication
Gene namesi
Name:HSPA5By similarity
Synonyms:GRP78By similarity
ORF Names:I79_019946Imported
OrganismiCricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus)
Taxonomic identifieri10029 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaCricetidaeCricetinaeCricetulus
Proteomesi
  • UP000001075 Componenti: Unassembled WGS sequence

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Endoplasmic reticulum

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi229T → A: Impaired ATPase activity. 3 Publications1
Mutagenesisi414 – 417LVLL → ADDA: Abolished homooligomerization. 1 Publication4
Mutagenesisi461V → F: Impaired substrate-binding. 3 Publications1
Mutagenesisi518T → A: Abolishes AMPylation. 1 Publication1
Mutagenesisi525T → A: Does not affect AMPylation. 1 Publication1
Mutagenesisi527T → A: Does not affect AMPylation. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 18By similarityAdd BLAST18
ChainiPRO_500344500419 – 654Endoplasmic reticulum chaperone BiPAdd BLAST636

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei86PhosphoserineBy similarity1
Modified residuei125N6-acetyllysineBy similarity1
Modified residuei160Nitrated tyrosineBy similarity1
Modified residuei213N6-acetyllysineBy similarity1
Modified residuei271N6-acetyllysineBy similarity1
Modified residuei326N6-acetyllysineBy similarity1
Cross-linki352Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)By similarity
Modified residuei353N6-acetyllysine; alternateBy similarity1
Cross-linki353Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1); alternateBy similarity
Modified residuei447N6-succinyllysineBy similarity1
Modified residuei492Omega-N-methylarginineBy similarity1
Modified residuei518O-AMP-threonine; alternate3 PublicationsImported1
Modified residuei518Phosphothreonine; alternateBy similarity1
Modified residuei585N6,N6,N6-trimethyllysine; by METTL21A; in vitroBy similarity1
Modified residuei585N6,N6-dimethyllysine; alternateBy similarity1
Modified residuei585N6-methyllysine; alternateBy similarity1
Modified residuei591N6-methyllysineBy similarity1
Modified residuei643PhosphothreonineBy similarity1
Modified residuei648PhosphothreonineBy similarity1
Modified residuei649PhosphoserineBy similarity1

Post-translational modificationi

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 (PubMed:26673894, PubMed:29198525, PubMed:29064369, PubMed:27918543). In response to endoplasmic reticulum stress, de-AMPylation by the same protein, FICD, restores the chaperone activity (PubMed:27918543).4 Publications

Keywords - PTMi

Acetylation, Isopeptide bond, Methylation, Nitration, Phosphoprotein, Ubl conjugation

Proteomic databases

PRIDEiG3I8R9

Interactioni

Subunit structurei

Monomer and homooligomer; homooligomerization via the interdomain linker inactivates the chaperone activity and acts as a storage of HSPA5/BiP molecules (PubMed:26473973). 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, UGT1A1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX (By similarity). Interacts with TMEM132A and TRIM21. May form a complex with ERLEC1, OS9, SEL1L and SYVN1. Interacts with DNAJC10 (By similarity). Interacts with DNAJB9/ERdj4; leading to recruit HSPA5/BiP to ERN1/IRE1 (PubMed:29198525). Interacts with ERN1/IRE1; interaction takes place following interaction with DNAJB9/ERdj4 and leads to inactivate ERN1/IRE1 (PubMed:29198525). Interacts with MX1 (By similarity). Interacts with METTL23. Interacts with CEMIP; the interaction induces calcium leakage from the endoplasmic reticulum and cell migration. Interacts with PCSK4 form; the interaction takes place in the endoplasmic reticulum. Interacts with CIPC. Interacts with CCDC88B (via C-terminus); the interaction opposes ERN1-mediated JNK activation, protecting against apoptosis. Interacts with INPP5K; necessary for INPP5K localization at the endoplasmic reticulum. Interacts with LOXL2; leading to activate the ERN1/IRE1-XBP1 pathway of the unfolded protein response (By similarity).By similarity2 Publications

Binary interactionsi

Protein-protein interaction databases

IntActiG3I8R9, 5 interactors

Structurei

Secondary structure

1654
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliG3I8R9
SMRiG3I8R9
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni125 – 280Nucleotide-binding (NBD)By similarityAdd BLAST156
Regioni409 – 419Interdomain linker1 PublicationAdd BLAST11
Regioni420 – 500Substrate-binding (SBD)By similarityAdd BLAST81

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi651 – 654Prevents secretion from ERSequence analysis4

Domaini

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.1 Publication

Sequence similaritiesi

Belongs to the heat shock protein 70 family.Curated

Keywords - Domaini

Signal

Phylogenomic databases

InParanoidiG3I8R9
KOiK09490

Family and domain databases

Gene3Di1.20.1270.10, 1 hit
2.60.34.10, 1 hit
InterProiView protein in InterPro
IPR018181 Heat_shock_70_CS
IPR029048 HSP70_C_sf
IPR029047 HSP70_peptide-bd_sf
IPR013126 Hsp_70_fam
PANTHERiPTHR19375 PTHR19375, 1 hit
PfamiView protein in Pfam
PF00012 HSP70, 1 hit
PRINTSiPR00301 HEATSHOCK70
SUPFAMiSSF100920 SSF100920, 1 hit
SSF100934 SSF100934, 1 hit
PROSITEiView protein in PROSITE
PS00297 HSP70_1, 1 hit
PS00329 HSP70_2, 1 hit
PS01036 HSP70_3, 1 hit

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

G3I8R9-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MKFPMVAAAL LLLCAVRAEE EDKKEDVGTV VGIDLGTTYS CVGVFKNGRV
60 70 80 90 100
EIIANDQGNR ITPSYVAFTP EGERLIGDAA KNQLTSNPEN TVFDAKRLIG
110 120 130 140 150
RTWNDPSVQQ DIKFLPFKVV EKKTKPYIQV DIGGGQTKTF APEEISAMVL
160 170 180 190 200
TKMKETAEAY LGKKVTHAVV TVPAYFNDAQ RQATKDAGTI AGLNVMRIIN
210 220 230 240 250
EPTAAAIAYG LDKREGEKNI LVFDLGGGTF DVSLLTIDNG VFEVVATNGD
260 270 280 290 300
THLGGEDFDQ RVMEHFIKLY KKKTGKDVRK DNRAVQKLRR EVEKAKRALS
310 320 330 340 350
SQHQARIEIE SFFEGEDFSE TLTRAKFEEL NMDLFRSTMK PVQKVLEDSD
360 370 380 390 400
LKKSDIDEIV LVGGSTRIPK IQQLVKEFFN GKEPSRGINP DEAVAYGAAV
410 420 430 440 450
QAGVLSGDQD TGDLVLLDVC PLTLGIETVG GVMTKLIPRN TVVPTKKSQI
460 470 480 490 500
FSTASDNQPT VTIKVYEGER PLTKDNHLLG TFDLTGIPPA PRGVPQIEVT
510 520 530 540 550
FEIDVNGILR VTAEDKGTGN KNKITITNDQ NRLTPEEIER MVNDAEKFAE
560 570 580 590 600
EDKKLKERID TRNELESYAY SLKNQIGDKE KLGGKLSSED KETMEKAVEE
610 620 630 640 650
KIEWLESHQD ADIEDFKAKK KELEEIVQPI ISKLYGSAGP PPTGEEDTSE

KDEL
Length:654
Mass (Da):72,379
Last modified:November 16, 2011 - v1
Checksum:i25CF665F59113A49
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
JH001529 Genomic DNA Translation: EGV94255.1
RefSeqiNP_001233668.1, NM_001246739.2

Genome annotation databases

GeneIDi100689305
KEGGicge:100689305

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
JH001529 Genomic DNA Translation: EGV94255.1
RefSeqiNP_001233668.1, NM_001246739.2

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5O4PX-ray1.86A/B28-549[»]
6EOBX-ray2.00A28-549[»]
6EOCX-ray1.67A28-549[»]
6EOEX-ray1.71A28-549[»]
6EOFX-ray1.59A28-549[»]
ProteinModelPortaliG3I8R9
SMRiG3I8R9
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiG3I8R9, 5 interactors

Proteomic databases

PRIDEiG3I8R9

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi100689305
KEGGicge:100689305

Organism-specific databases

CTDi3309

Phylogenomic databases

InParanoidiG3I8R9
KOiK09490

Family and domain databases

Gene3Di1.20.1270.10, 1 hit
2.60.34.10, 1 hit
InterProiView protein in InterPro
IPR018181 Heat_shock_70_CS
IPR029048 HSP70_C_sf
IPR029047 HSP70_peptide-bd_sf
IPR013126 Hsp_70_fam
PANTHERiPTHR19375 PTHR19375, 1 hit
PfamiView protein in Pfam
PF00012 HSP70, 1 hit
PRINTSiPR00301 HEATSHOCK70
SUPFAMiSSF100920 SSF100920, 1 hit
SSF100934 SSF100934, 1 hit
PROSITEiView protein in PROSITE
PS00297 HSP70_1, 1 hit
PS00329 HSP70_2, 1 hit
PS01036 HSP70_3, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiBIP_CRIGR
AccessioniPrimary (citable) accession number: G3I8R9
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 28, 2018
Last sequence update: November 16, 2011
Last modified: November 7, 2018
This is version 52 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
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Main funding by: National Institutes of Health

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