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Protein

Endoplasmic reticulum chaperone BiP

Gene

HSPA5

Organism
Bos taurus (Bovine)
Status
Reviewed-Annotation score: -Experimental evidence at transcript 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). 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. 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).By similarity

Catalytic activityi

ATP + H2O = ADP + phosphate.By similarity

Enzyme 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 functionHydrolase
LigandATP-binding, Nucleotide-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Endoplasmic reticulum chaperone BiPBy similarity (EC:3.6.4.10By similarity)
Alternative name(s):
78 kDa glucose-regulated proteinBy similarity
Short name:
GRP-78By similarity
Binding-immunoglobulin proteinBy similarity
Short name:
BiPBy similarity
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 proteinBy similarity
Gene namesi
Name:HSPA5By similarity
Synonyms:GRP78By similarity
OrganismiBos taurus (Bovine)
Taxonomic identifieri9913 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos
Proteomesi
  • UP000009136 Componenti: Unplaced

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

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 19By similarityAdd BLAST19
ChainiPRO_000028877420 – 655Endoplasmic reticulum chaperone BiPAdd BLAST636

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei87PhosphoserineBy similarity1
Modified residuei126N6-acetyllysineBy similarity1
Modified residuei161Nitrated tyrosineBy similarity1
Modified residuei214N6-acetyllysineBy similarity1
Modified residuei272N6-acetyllysineBy similarity1
Modified residuei327N6-acetyllysineBy similarity1
Cross-linki353Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)By similarity
Modified residuei354N6-acetyllysine; alternateBy similarity1
Cross-linki354Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1); alternateBy similarity
Modified residuei448N6-succinyllysineBy similarity1
Modified residuei493Omega-N-methylarginineBy similarity1
Modified residuei519O-AMP-threonineBy similarity1
Modified residuei519PhosphothreonineBy similarity1
Modified residuei586N6,N6,N6-trimethyllysine; by METTL21A; in vitroBy similarity1
Modified residuei586N6,N6-dimethyllysine; alternateBy similarity1
Modified residuei586N6-methyllysine; alternateBy similarity1
Modified residuei592N6-methyllysineBy similarity1
Modified residuei644PhosphothreonineBy similarity1

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

PaxDbiQ0VCX2
PeptideAtlasiQ0VCX2
PRIDEiQ0VCX2

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) (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. Interacts with ERN1/IRE1; interaction takes place following interaction with DNAJB9/ERdj4 and leads to inactivate ERN1/IRE1 (By similarity). 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 similarity

Protein-protein interaction databases

DIPiDIP-60411N
IntActiQ0VCX2, 2 interactors
STRINGi9913.ENSBTAP00000052422

Structurei

3D structure databases

ProteinModelPortaliQ0VCX2
SMRiQ0VCX2
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 ERPROSITE-ProRule annotation4

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

HOVERGENiHBG051845
InParanoidiQ0VCX2
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
PS00014 ER_TARGET, 1 hit
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.

Q0VCX2-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MKLSLVAAVL LLLLGTARAE EEDKKEDVGT VVGIDLGTTY SCVGVFKNGR
60 70 80 90 100
VEIIANDQGN RITPSYVAFT PEGERLIGDA AKNQLTSNPE NTVFDAKRLI
110 120 130 140 150
GRTWNDPSVQ QDIKFLPFKV VEKKTKPYIQ VDVGGGQTKT 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 ESFYEGEDFS 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 IISKLYGSAG PPPTSEEEAA

DKDEL
Length:655
Mass (Da):72,400
Last modified:September 5, 2006 - v1
Checksum:i93B4C3D46A441066
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BT030726 mRNA Translation: ABS45042.1
BC119953 mRNA Translation: AAI19954.1
RefSeqiNP_001068616.1, NM_001075148.1
UniGeneiBt.65104

Genome annotation databases

GeneIDi415113
KEGGibta:415113

Similar proteinsi

Entry informationi

Entry nameiBIP_BOVIN
AccessioniPrimary (citable) accession number: Q0VCX2
Secondary accession number(s): A7E3V5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 29, 2007
Last sequence update: September 5, 2006
Last modified: April 25, 2018
This is version 86 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

Complete proteome, Reference proteome
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Main funding by: National Institutes of Health