BIP_BOVIN
ID BIP_BOVIN Reviewed; 655 AA.
AC Q0VCX2; A7E3V5;
DT 29-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 05-SEP-2006, sequence version 1.
DT 03-AUG-2022, entry version 111.
DE RecName: Full=Endoplasmic reticulum chaperone BiP {ECO:0000250|UniProtKB:P11021};
DE EC=3.6.4.10 {ECO:0000250|UniProtKB:P11021};
DE AltName: Full=78 kDa glucose-regulated protein {ECO:0000250|UniProtKB:P11021};
DE Short=GRP-78 {ECO:0000250|UniProtKB:P11021};
DE AltName: Full=Binding-immunoglobulin protein {ECO:0000250|UniProtKB:P11021};
DE Short=BiP {ECO:0000250|UniProtKB:P11021};
DE AltName: Full=Heat shock protein 70 family protein 5 {ECO:0000250|UniProtKB:P11021};
DE Short=HSP70 family protein 5 {ECO:0000250|UniProtKB:P11021};
DE AltName: Full=Heat shock protein family A member 5 {ECO:0000250|UniProtKB:P11021};
DE AltName: Full=Immunoglobulin heavy chain-binding protein {ECO:0000250|UniProtKB:P11021};
DE Flags: Precursor;
GN Name=HSPA5 {ECO:0000250|UniProtKB:P11021};
GN Synonyms=GRP78 {ECO:0000250|UniProtKB:P11021};
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=16305752; DOI=10.1186/1471-2164-6-166;
RA Harhay G.P., Sonstegard T.S., Keele J.W., Heaton M.P., Clawson M.L.,
RA Snelling W.M., Wiedmann R.T., Van Tassell C.P., Smith T.P.L.;
RT "Characterization of 954 bovine full-CDS cDNA sequences.";
RL BMC Genomics 6:166-166(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Hereford; TISSUE=Fetal skin;
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (AUG-2006) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Endoplasmic reticulum chaperone that plays a key role in
CC protein folding and quality control in the endoplasmic reticulum lumen
CC (By similarity). Involved in the correct folding of proteins and
CC degradation of misfolded proteins via its interaction with
CC DNAJC10/ERdj5, probably to facilitate the release of DNAJC10/ERdj5 from
CC its substrate (By similarity). Acts as a key repressor of the
CC ERN1/IRE1-mediated unfolded protein response (UPR). In the unstressed
CC endoplasmic reticulum, recruited by DNAJB9/ERdj4 to the luminal region
CC of ERN1/IRE1, leading to disrupt the dimerization of ERN1/IRE1, thereby
CC inactivating ERN1/IRE1. Accumulation of misfolded protein in the
CC endoplasmic reticulum causes release of HSPA5/BiP from ERN1/IRE1,
CC allowing homodimerization and subsequent activation of ERN1/IRE1 (By
CC similarity). Plays an auxiliary role in post-translational transport of
CC small presecretory proteins across endoplasmic reticulum (ER). May
CC function as an allosteric modulator for SEC61 channel-forming
CC translocon complex, likely cooperating with SEC62 to enable the
CC productive insertion of these precursors into SEC61 channel. Appears to
CC specifically regulate translocation of precursors having inhibitory
CC residues in their mature region that weaken channel gating. May also
CC play a role in apoptosis and cell proliferation (By similarity).
CC {ECO:0000250|UniProtKB:G3I8R9, ECO:0000250|UniProtKB:P11021,
CC ECO:0000250|UniProtKB:P20029}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.10;
CC Evidence={ECO:0000250|UniProtKB:G3I8R9};
CC -!- ACTIVITY REGULATION: The chaperone activity is regulated by ATP-induced
CC allosteric coupling of the nucleotide-binding (NBD) and substrate-
CC binding (SBD) domains (By similarity). In the ADP-bound and nucleotide-
CC free (apo) states, the two domains have little interaction (By
CC similarity). In contrast, in the ATP-bound state the two domains are
CC tightly coupled, which results in drastically accelerated kinetics in
CC both binding and release of polypeptide substrates (By similarity). J
CC domain-containing co-chaperones (DNAJB9/ERdj4 or DNAJC10/ERdj5)
CC stimulate the ATPase activity and are required for efficient substrate
CC recognition by HSPA5/BiP. Homooligomerization inactivates participating
CC HSPA5/BiP protomers and probably act as reservoirs to store HSPA5/BiP
CC molecules when they are not needed by the cell (By similarity).
CC {ECO:0000250|UniProtKB:G3I8R9, ECO:0000250|UniProtKB:P11021}.
CC -!- SUBUNIT: Monomer and homooligomer; homooligomerization via the
CC interdomain linker inactivates the chaperone activity and acts as a
CC storage of HSPA5/BiP molecules (By similarity). Interacts with DNAJC1
CC (via J domain). Component of an EIF2 complex at least composed of
CC CELF1/CUGBP1, CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5. Part of a
CC large chaperone multiprotein complex comprising DNAJB11, HSP90B1,
CC HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small
CC amounts of ERP29, but not, or at very low levels, CALR nor CANX (By
CC similarity). Interacts with TMEM132A and TRIM21 (By similarity). May
CC form a complex with ERLEC1, OS9, SEL1L and SYVN1 (By similarity).
CC Interacts with DNAJC10. Interacts with DNAJB9/ERdj4; leading to recruit
CC HSPA5/BiP to ERN1/IRE1 (By similarity). Interacts with ERN1/IRE1;
CC interaction takes place following interaction with DNAJB9/ERdj4 and
CC leads to inactivate ERN1/IRE1 (By similarity). Interacts with MX1 (By
CC similarity). Interacts with METTL23 (By similarity). Interacts with
CC CEMIP; the interaction induces calcium leakage from the endoplasmic
CC reticulum and cell migration (By similarity). Interacts with PCSK4
CC form; the interaction takes place in the endoplasmic reticulum (By
CC similarity). Interacts with CIPC (By similarity). Interacts with
CC CCDC88B (via C-terminus); the interaction opposes ERN1-mediated JNK
CC activation, protecting against apoptosis (By similarity). Interacts
CC with INPP5K; necessary for INPP5K localization at the endoplasmic
CC reticulum (By similarity). Interacts with MANF; the interaction is
CC direct (By similarity). Interacts with LOXL2; leading to activate the
CC ERN1/IRE1-XBP1 pathway of the unfolded protein response (By
CC similarity). Interacts with CLU under stressed condition; interaction
CC increases CLU protein stability; facilitates its retrotranslocation and
CC redistribution to the mitochondria; cooperatively suppress stress-
CC induced apoptosis by stabilizing mitochondrial membrane integrity (By
CC similarity). Interacts with CCDC47 (By similarity). Interacts with CLN3
CC (By similarity). Interacts with KIAA1324; may regulate the function of
CC HSPA5 in apoptosis and cell proliferation. Interacts with CASP7 (By
CC similarity). Interacts with ILDR2; the interaction stabilizes ILDR2
CC expression (By similarity). {ECO:0000250|UniProtKB:G3I8R9,
CC ECO:0000250|UniProtKB:P11021, ECO:0000250|UniProtKB:P20029}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
CC {ECO:0000250|UniProtKB:P11021}. Melanosome
CC {ECO:0000250|UniProtKB:P11021}. Cytoplasm
CC {ECO:0000250|UniProtKB:P20029}. Cell surface. Note=Identified by mass
CC spectrometry in melanosome fractions from stage I to stage IV (By
CC similarity). Localizes to the cell surface in epithelial cells; high
CC levels of free iron promotes cell surface localization (By similarity).
CC {ECO:0000250|UniProtKB:P11021}.
CC -!- DOMAIN: The interdomain linker regulates the chaperone activity by
CC mediating the formation of homooligomers. Homooligomers are formed by
CC engagement of the interdomain linker of one HSPA5/BiP molecule as a
CC typical substrate of an adjacent HSPA5/BiP molecule. HSPA5/BiP
CC oligomerization inactivates participating HSPA5/BiP protomers.
CC HSPA5/BiP oligomers probably act as reservoirs to store HSPA5/BiP
CC molecules when they are not needed by the cell. When the levels of
CC unfolded proteins rise, cells can rapidly break up these oligomers to
CC make active monomers. {ECO:0000250|UniProtKB:G3I8R9}.
CC -!- PTM: In unstressed cells, AMPylation at Thr-519 by FICD inactivates the
CC chaperome activity: AMPylated form is locked in a relatively inert
CC state and only weakly stimulated by J domain-containing proteins. In
CC response to endoplasmic reticulum stress, de-AMPylation by the same
CC protein, FICD, restores the chaperone activity.
CC {ECO:0000250|UniProtKB:G3I8R9}.
CC -!- SIMILARITY: Belongs to the heat shock protein 70 family. {ECO:0000305}.
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DR EMBL; BT030726; ABS45042.1; -; mRNA.
DR EMBL; BC119953; AAI19954.1; -; mRNA.
DR RefSeq; NP_001068616.1; NM_001075148.1.
DR AlphaFoldDB; Q0VCX2; -.
DR SMR; Q0VCX2; -.
DR DIP; DIP-60411N; -.
DR IntAct; Q0VCX2; 2.
DR STRING; 9913.ENSBTAP00000052422; -.
DR PaxDb; Q0VCX2; -.
DR PeptideAtlas; Q0VCX2; -.
DR PRIDE; Q0VCX2; -.
DR Ensembl; ENSBTAT00000057533; ENSBTAP00000052422; ENSBTAG00000007662.
DR GeneID; 415113; -.
DR KEGG; bta:415113; -.
DR CTD; 3309; -.
DR VEuPathDB; HostDB:ENSBTAG00000007662; -.
DR VGNC; VGNC:59220; HSPA5.
DR eggNOG; KOG0100; Eukaryota.
DR GeneTree; ENSGT00940000154787; -.
DR InParanoid; Q0VCX2; -.
DR OMA; AYTKNQD; -.
DR OrthoDB; 288077at2759; -.
DR PRO; PR:Q0VCX2; -.
DR Proteomes; UP000009136; Chromosome 11.
DR Bgee; ENSBTAG00000007662; Expressed in spermatid and 101 other tissues.
DR GO; GO:0009986; C:cell surface; IEA:UniProtKB-SubCell.
DR GO; GO:0008180; C:COP9 signalosome; IEA:Ensembl.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0034663; C:endoplasmic reticulum chaperone complex; IBA:GO_Central.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; IBA:GO_Central.
DR GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; IEA:Ensembl.
DR GO; GO:0030176; C:integral component of endoplasmic reticulum membrane; IEA:Ensembl.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISS:UniProtKB.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0030496; C:midbody; IEA:Ensembl.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IBA:GO_Central.
DR GO; GO:0016887; F:ATP hydrolysis activity; ISS:UniProtKB.
DR GO; GO:0140662; F:ATP-dependent protein folding chaperone; IEA:InterPro.
DR GO; GO:0031072; F:heat shock protein binding; IBA:GO_Central.
DR GO; GO:0051787; F:misfolded protein binding; IBA:GO_Central.
DR GO; GO:0019904; F:protein domain specific binding; IEA:Ensembl.
DR GO; GO:0044183; F:protein folding chaperone; IBA:GO_Central.
DR GO; GO:0043022; F:ribosome binding; IEA:Ensembl.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IEA:Ensembl.
DR GO; GO:0051082; F:unfolded protein binding; IBA:GO_Central.
DR GO; GO:0042149; P:cellular response to glucose starvation; IEA:Ensembl.
DR GO; GO:0071353; P:cellular response to interleukin-4; IEA:Ensembl.
DR GO; GO:0034620; P:cellular response to unfolded protein; IBA:GO_Central.
DR GO; GO:0021680; P:cerebellar Purkinje cell layer development; IEA:Ensembl.
DR GO; GO:0021589; P:cerebellum structural organization; IEA:Ensembl.
DR GO; GO:0051085; P:chaperone cofactor-dependent protein refolding; IBA:GO_Central.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IBA:GO_Central.
DR GO; GO:0006983; P:ER overload response; IEA:Ensembl.
DR GO; GO:0035437; P:maintenance of protein localization in endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:1903895; P:negative regulation of IRE1-mediated unfolded protein response; ISS:UniProtKB.
DR GO; GO:0031333; P:negative regulation of protein-containing complex assembly; ISS:UniProtKB.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0030335; P:positive regulation of cell migration; ISS:UniProtKB.
DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IEA:Ensembl.
DR GO; GO:0031204; P:post-translational protein targeting to membrane, translocation; ISS:UniProtKB.
DR GO; GO:0042026; P:protein refolding; IBA:GO_Central.
DR GO; GO:1901998; P:toxin transport; IEA:Ensembl.
DR GO; GO:0030433; P:ubiquitin-dependent ERAD pathway; IBA:GO_Central.
DR CDD; cd10241; HSPA5-like_NBD; 1.
DR Gene3D; 1.20.1270.10; -; 1.
DR Gene3D; 2.60.34.10; -; 1.
DR InterPro; IPR043129; ATPase_NBD.
DR InterPro; IPR042050; BIP_NBD.
DR InterPro; IPR018181; Heat_shock_70_CS.
DR InterPro; IPR029048; HSP70_C_sf.
DR InterPro; IPR029047; HSP70_peptide-bd_sf.
DR InterPro; IPR013126; Hsp_70_fam.
DR PANTHER; PTHR19375; PTHR19375; 1.
DR Pfam; PF00012; HSP70; 1.
DR SUPFAM; SSF100920; SSF100920; 1.
DR SUPFAM; SSF100934; SSF100934; 1.
DR SUPFAM; SSF53067; SSF53067; 2.
DR PROSITE; PS00014; ER_TARGET; 1.
DR PROSITE; PS00297; HSP70_1; 1.
DR PROSITE; PS00329; HSP70_2; 1.
DR PROSITE; PS01036; HSP70_3; 1.
PE 2: Evidence at transcript level;
KW Acetylation; ATP-binding; Chaperone; Cytoplasm; Endoplasmic reticulum;
KW Hydrolase; Isopeptide bond; Methylation; Nitration; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Signal; Ubl conjugation.
FT SIGNAL 1..19
FT /evidence="ECO:0000250"
FT CHAIN 20..655
FT /note="Endoplasmic reticulum chaperone BiP"
FT /id="PRO_0000288774"
FT REGION 1..81
FT /note="Required for interaction with KIAA1324"
FT /evidence="ECO:0000250|UniProtKB:P11021"
FT REGION 126..281
FT /note="Nucleotide-binding (NBD)"
FT /evidence="ECO:0000250|UniProtKB:P11021"
FT REGION 410..420
FT /note="Interdomain linker"
FT /evidence="ECO:0000250|UniProtKB:G3I8R9"
FT REGION 421..501
FT /note="Substrate-binding (SBD)"
FT /evidence="ECO:0000250|UniProtKB:P11021"
FT REGION 635..655
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 652..655
FT /note="Prevents secretion from ER"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10138"
FT BINDING 37..40
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P11021"
FT BINDING 97
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P11021"
FT BINDING 228..230
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P11021"
FT BINDING 294..301
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P11021"
FT BINDING 365..368
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P11021"
FT MOD_RES 87
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P06761"
FT MOD_RES 126
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P20029"
FT MOD_RES 161
FT /note="3'-nitrotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P20029"
FT MOD_RES 214
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P20029"
FT MOD_RES 272
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P0DMV8"
FT MOD_RES 327
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P20029"
FT MOD_RES 354
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P20029"
FT MOD_RES 448
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:P20029"
FT MOD_RES 493
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:P0DMV8"
FT MOD_RES 519
FT /note="O-AMP-threonine; alternate"
FT /evidence="ECO:0000250|UniProtKB:G3I8R9"
FT MOD_RES 519
FT /note="Phosphothreonine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P11021"
FT MOD_RES 586
FT /note="N6,N6,N6-trimethyllysine; by METTL21A; in vitro"
FT /evidence="ECO:0000250|UniProtKB:P0DMV8"
FT MOD_RES 586
FT /note="N6,N6-dimethyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P11021"
FT MOD_RES 586
FT /note="N6-methyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P11021"
FT MOD_RES 592
FT /note="N6-methyllysine"
FT /evidence="ECO:0000250|UniProtKB:P11021"
FT MOD_RES 644
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P20029"
FT CROSSLNK 353
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:P11021"
FT CROSSLNK 354
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1); alternate"
FT /evidence="ECO:0000250|UniProtKB:P11021"
SQ SEQUENCE 655 AA; 72400 MW; 93B4C3D46A441066 CRC64;
MKLSLVAAVL LLLLGTARAE EEDKKEDVGT VVGIDLGTTY SCVGVFKNGR VEIIANDQGN
RITPSYVAFT PEGERLIGDA AKNQLTSNPE NTVFDAKRLI GRTWNDPSVQ QDIKFLPFKV
VEKKTKPYIQ VDVGGGQTKT FAPEEISAMV LTKMKETAEA YLGKKVTHAV VTVPAYFNDA
QRQATKDAGT IAGLNVMRII NEPTAAAIAY GLDKREGEKN ILVFDLGGGT FDVSLLTIDN
GVFEVVATNG DTHLGGEDFD QRVMEHFIKL YKKKTGKDVR KDNRAVQKLR REVEKAKRAL
SSQHQARIEI ESFYEGEDFS ETLTRAKFEE LNMDLFRSTM KPVQKVLEDS DLKKSDIDEI
VLVGGSTRIP KIQQLVKEFF NGKEPSRGIN PDEAVAYGAA VQAGVLSGDQ DTGDLVLLDV
CPLTLGIETV GGVMTKLIPR NTVVPTKKSQ IFSTASDNQP TVTIKVYEGE RPLTKDNHLL
GTFDLTGIPP APRGVPQIEV TFEIDVNGIL RVTAEDKGTG NKNKITITND QNRLTPEEIE
RMVNDAEKFA EEDKKLKERI DTRNELESYA YSLKNQIGDK EKLGGKLSSE DKETMEKAVE
EKIEWLESHQ DADIEDFKAK KKELEEIVQP IISKLYGSAG PPPTSEEEAA DKDEL
