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Protein

Endoplasmic reticulum chaperone BiP

Gene

Hspa5

Organism
Mus musculus (Mouse)
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 (PubMed:12411443, PubMed:12475965). 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 (PubMed:12411443). Acts as a key repressor of the ERN1/IRE1-mediated unfolded protein response (UPR) (By similarity). 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.By similarity2 Publications

Catalytic activityi

ATP + H2O = ADP + phosphate.By similarity

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. 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).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei97ATPBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi37 – 40ATPBy similarity4
Nucleotide bindingi228 – 230ATPBy similarity3
Nucleotide bindingi294 – 301ATPBy similarity8
Nucleotide bindingi365 – 368ATPBy similarity4

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionChaperone, Hydrolase
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-MMU-3371453 Regulation of HSF1-mediated heat shock response
R-MMU-983170 Antigen Presentation: Folding, assembly and peptide loading of class I MHC

Names & Taxonomyi

Protein namesi
Recommended name:
Endoplasmic reticulum chaperone BiPCurated (EC:3.6.4.10By similarity)
Alternative name(s):
78 kDa glucose-regulated protein1 Publication
Short name:
GRP-781 Publication
Binding-immunoglobulin protein1 Publication
Short name:
BiP1 Publication
Heat shock protein 70 family protein 5Curated
Short name:
HSP70 family protein 5Curated
Heat shock protein family A member 5Imported
Immunoglobulin heavy chain-binding protein1 Publication
Gene namesi
Name:Hspa5Imported
Synonyms:Grp781 Publication
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 2

Organism-specific databases

MGIiMGI:95835 Hspa5

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

Cytoplasm, Endoplasmic reticulum

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 192 PublicationsAdd BLAST19
ChainiPRO_000001356820 – 655Endoplasmic reticulum chaperone BiPAdd BLAST636

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei87PhosphoserineBy similarity1
Modified residuei126N6-acetyllysineCombined sources1
Modified residuei161Nitrated tyrosineCombined sources1
Modified residuei214N6-acetyllysineCombined sources1
Modified residuei272N6-acetyllysineBy similarity1
Modified residuei327N6-acetyllysineCombined sources1
Cross-linki353Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)By similarity
Modified residuei354N6-acetyllysine; alternateCombined sources1
Cross-linki354Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1); alternateBy similarity
Modified residuei448N6-succinyllysineCombined sources1
Modified residuei493Omega-N-methylarginineBy similarity1
Modified residuei519O-AMP-threonine; alternateBy similarity1
Modified residuei519Phosphothreonine; alternateBy similarity1
Modified residuei586N6,N6,N6-trimethyllysine; by METTL21A; in vitro1 Publication1
Modified residuei586N6,N6-dimethyllysine; alternateBy similarity1
Modified residuei586N6-methyllysine; alternateBy similarity1
Modified residuei592N6-methyllysineBy similarity1
Modified residuei644PhosphothreonineCombined sources1
Modified residuei649PhosphothreonineCombined sources1
Modified residuei650PhosphoserineCombined sources1

Post-translational modificationi

In unstressed cells, AMPylation at Thr-519 by FICD inactivates the chaperome activity: AMPylated form is locked in a relatively inert state and only weakly stimulated by J domain-containing proteins. In response to endoplasmic reticulum stress, de-AMPylation by the same protein, FICD, restores the chaperone activity.By similarity

Keywords - PTMi

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

Proteomic databases

EPDiP20029
MaxQBiP20029
PaxDbiP20029
PeptideAtlasiP20029
PRIDEiP20029
TopDownProteomicsiP20029

2D gel databases

COMPLUYEAST-2DPAGEiP20029
REPRODUCTION-2DPAGEiIPI00319992
P20029
SWISS-2DPAGEiP20029
UCD-2DPAGEiP20029

PTM databases

CarbonylDBiP20029
iPTMnetiP20029
PhosphoSitePlusiP20029
SwissPalmiP20029

Expressioni

Gene expression databases

BgeeiENSMUSG00000026864 Expressed in 301 organ(s), highest expression level in prostate gland
CleanExiMM_HSPA5
ExpressionAtlasiP20029 baseline and differential
GenevisibleiP20029 MM

Interactioni

Subunit structurei

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) (PubMed:12065409). Component of an EIF2 complex at least composed of CELF1/CUGBP1, CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5 (PubMed:16931514). 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 (PubMed:12475965). Interacts with TMEM132A and TRIM21 (By similarity). May form a complex with ERLEC1, OS9, SEL1L and SYVN1 (By similarity). Interacts with DNAJC10 (PubMed:12411443). Interacts with DNAJB9/ERdj4; leading to recruit HSPA5/BiP to ERN1/IRE1 (PubMed:11836248). Interacts with ERN1/IRE1; interaction takes place following interaction with DNAJB9/ERdj4 and leads to inactivate ERN1/IRE1 (By similarity). Interacts with MX1 (PubMed:21992152). Interacts with METTL23 (By similarity). Interacts with CEMIP; the interaction induces calcium leakage from the endoplasmic reticulum and cell migration (By similarity). Interacts with PCSK4 form; the interaction takes place in the endoplasmic reticulum (By similarity). Interacts with CIPC (By similarity). Interacts with CCDC88B (via C-terminus); the interaction opposes ERN1-mediated JNK activation, protecting against apoptosis (By similarity). Interacts with INPP5K; necessary for INPP5K localization at the endoplasmic reticulum (By similarity). Interacts with MANF; the interaction is direct (By similarity). Interacts with LOXL2; leading to activate the ERN1/IRE1-XBP1 pathway of the unfolded protein response (By similarity).By similarity6 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi200078, 44 interactors
CORUMiP20029
DIPiDIP-32341N
IntActiP20029, 33 interactors
MINTiP20029
STRINGi10090.ENSMUSP00000028222

Structurei

3D structure databases

ProteinModelPortaliP20029
SMRiP20029
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni126 – 281Nucleotide-binding (NBD)By similarityAdd BLAST156
Regioni410 – 420Interdomain linkerBy similarityAdd BLAST11
Regioni421 – 501Substrate-binding (SBD)By similarityAdd BLAST81

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi652 – 655Prevents secretion from ER4

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.By similarity

Sequence similaritiesi

Belongs to the heat shock protein 70 family.Curated

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiKOG0101 Eukaryota
COG0443 LUCA
GeneTreeiENSGT00930000150862
HOGENOMiHOG000228135
HOVERGENiHBG051845
InParanoidiP20029
KOiK09490
OMAiCVGVMQK
OrthoDBiEOG091G0352
PhylomeDBiP20029
TreeFamiTF105044

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
PS00014 ER_TARGET, 1 hit
PS00297 HSP70_1, 1 hit
PS00329 HSP70_2, 1 hit
PS01036 HSP70_3, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

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

This entry has 1 described isoform and 1 potential isoform that is computationally mapped.Show allAlign All

P20029-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MMKFTVVAAA LLLLGAVRAE EEDKKEDVGT VVGIDLGTTY SCVGVFKNGR
60 70 80 90 100
VEIIANDQGN RITPSYVAFT PEGERLIGDA AKNQLTSNPE NTVFDAKRLI
110 120 130 140 150
GRTWNDPSVQ QDIKFLPFKV VEKKTKPYIQ VDIGGGQTKT FAPEEISAMV
160 170 180 190 200
LTKMKETAEA YLGKKVTHAV VTVPAYFNDA QRQATKDAGT IAGLNVMRII
210 220 230 240 250
NEPTAAAIAY GLDKREGEKN ILVFDLGGGT FDVSLLTIDN GVFEVVATNG
260 270 280 290 300
DTHLGGEDFD QRVMEHFIKL YKKKTGKDVR KDNRAVQKLR REVEKAKRAL
310 320 330 340 350
SSQHQARIEI ESFFEGEDFS ETLTRAKFEE LNMDLFRSTM KPVQKVLEDS
360 370 380 390 400
DLKKSDIDEI VLVGGSTRIP KIQQLVKEFF NGKEPSRGIN PDEAVAYGAA
410 420 430 440 450
VQAGVLSGDQ DTGDLVLLDV CPLTLGIETV GGVMTKLIPR NTVVPTKKSQ
460 470 480 490 500
IFSTASDNQP TVTIKVYEGE RPLTKDNHLL GTFDLTGIPP APRGVPQIEV
510 520 530 540 550
TFEIDVNGIL RVTAEDKGTG NKNKITITND QNRLTPEEIE RMVNDAEKFA
560 570 580 590 600
EEDKKLKERI DTRNELESYA YSLKNQIGDK EKLGGKLSSE DKETMEKAVE
610 620 630 640 650
EKIEWLESHQ DADIEDFKAK KKELEEIVQP IISKLYGSGG PPPTGEEDTS

EKDEL
Length:655
Mass (Da):72,422
Last modified:November 1, 1997 - v3
Checksum:iAFB795D15E20FAC2
GO

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
A0A0A6YXF5A0A0A6YXF5_MOUSE
Endoplasmic reticulum chaperone BiP
Hspa5
42Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti43V → F in BAA11462 (PubMed:8645260).Curated1
Sequence conflicti245V → W in BAA11462 (PubMed:8645260).Curated1
Sequence conflicti329E → G in BAA11462 (PubMed:8645260).Curated1
Sequence conflicti361V → A in BAA11462 (PubMed:8645260).Curated1
Sequence conflicti474T → R in CAA05361 (PubMed:2895472).Curated1
Sequence conflicti591D → G in AAA37742 (PubMed:2583523).Curated1
Sequence conflicti596E → K AA sequence (PubMed:2559088).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ002387 mRNA Translation: CAA05361.1
M19351 mRNA Translation: AAA37315.1
D78645 mRNA Translation: BAA11462.1
AK076079 mRNA Translation: BAC36166.1
AK146647 mRNA Translation: BAE27328.1
AK148539 mRNA Translation: BAE28609.1
AK151647 mRNA Translation: BAE30576.1
AK152020 mRNA Translation: BAE30882.1
AK166739 mRNA Translation: BAE38982.1
AK169034 mRNA Translation: BAE40825.1
BC050927 mRNA Translation: AAH50927.1
U16277 Genomic DNA Translation: AAA76734.1
M30779 mRNA Translation: AAA37742.1
CCDSiCCDS15950.1
PIRiA37048
RefSeqiNP_001156906.1, NM_001163434.1
NP_071705.3, NM_022310.3
UniGeneiMm.330160
Mm.470180
Mm.474909

Genome annotation databases

EnsembliENSMUST00000028222; ENSMUSP00000028222; ENSMUSG00000026864
ENSMUST00000100171; ENSMUSP00000097747; ENSMUSG00000026864
GeneIDi14828
KEGGimmu:14828
UCSCiuc008jis.2 mouse

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ002387 mRNA Translation: CAA05361.1
M19351 mRNA Translation: AAA37315.1
D78645 mRNA Translation: BAA11462.1
AK076079 mRNA Translation: BAC36166.1
AK146647 mRNA Translation: BAE27328.1
AK148539 mRNA Translation: BAE28609.1
AK151647 mRNA Translation: BAE30576.1
AK152020 mRNA Translation: BAE30882.1
AK166739 mRNA Translation: BAE38982.1
AK169034 mRNA Translation: BAE40825.1
BC050927 mRNA Translation: AAH50927.1
U16277 Genomic DNA Translation: AAA76734.1
M30779 mRNA Translation: AAA37742.1
CCDSiCCDS15950.1
PIRiA37048
RefSeqiNP_001156906.1, NM_001163434.1
NP_071705.3, NM_022310.3
UniGeneiMm.330160
Mm.470180
Mm.474909

3D structure databases

ProteinModelPortaliP20029
SMRiP20029
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi200078, 44 interactors
CORUMiP20029
DIPiDIP-32341N
IntActiP20029, 33 interactors
MINTiP20029
STRINGi10090.ENSMUSP00000028222

PTM databases

CarbonylDBiP20029
iPTMnetiP20029
PhosphoSitePlusiP20029
SwissPalmiP20029

2D gel databases

COMPLUYEAST-2DPAGEiP20029
REPRODUCTION-2DPAGEiIPI00319992
P20029
SWISS-2DPAGEiP20029
UCD-2DPAGEiP20029

Proteomic databases

EPDiP20029
MaxQBiP20029
PaxDbiP20029
PeptideAtlasiP20029
PRIDEiP20029
TopDownProteomicsiP20029

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000028222; ENSMUSP00000028222; ENSMUSG00000026864
ENSMUST00000100171; ENSMUSP00000097747; ENSMUSG00000026864
GeneIDi14828
KEGGimmu:14828
UCSCiuc008jis.2 mouse

Organism-specific databases

CTDi3309
MGIiMGI:95835 Hspa5

Phylogenomic databases

eggNOGiKOG0101 Eukaryota
COG0443 LUCA
GeneTreeiENSGT00930000150862
HOGENOMiHOG000228135
HOVERGENiHBG051845
InParanoidiP20029
KOiK09490
OMAiCVGVMQK
OrthoDBiEOG091G0352
PhylomeDBiP20029
TreeFamiTF105044

Enzyme and pathway databases

ReactomeiR-MMU-3371453 Regulation of HSF1-mediated heat shock response
R-MMU-983170 Antigen Presentation: Folding, assembly and peptide loading of class I MHC

Miscellaneous databases

ChiTaRSiHspa5 mouse
PROiPR:P20029
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000026864 Expressed in 301 organ(s), highest expression level in prostate gland
CleanExiMM_HSPA5
ExpressionAtlasiP20029 baseline and differential
GenevisibleiP20029 MM

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
PS00014 ER_TARGET, 1 hit
PS00297 HSP70_1, 1 hit
PS00329 HSP70_2, 1 hit
PS01036 HSP70_3, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiBIP_MOUSE
AccessioniPrimary (citable) accession number: P20029
Secondary accession number(s): O35642, Q3UFF2, Q61630
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1991
Last sequence update: November 1, 1997
Last modified: November 7, 2018
This is version 196 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
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Main funding by: National Institutes of Health

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