BIP_DROME
ID BIP_DROME Reviewed; 656 AA.
AC P29844; A4V4C4; Q86NM3; Q9VYU2; Q9VYU3;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 2.
DT 03-AUG-2022, entry version 171.
DE RecName: Full=Endoplasmic reticulum chaperone BiP {ECO:0000305};
DE EC=3.6.4.10;
DE AltName: Full=78 kDa glucose-regulated protein homolog {ECO:0000250|UniProtKB:P11021};
DE Short=GRP-78 homolog {ECO:0000250|UniProtKB:P11021};
DE AltName: Full=Binding-immunoglobulin protein homolog {ECO:0000250|UniProtKB:P11021};
DE Short=BiP {ECO:0000250|UniProtKB:P11021};
DE AltName: Full=Heat shock 70 kDa protein cognate 3 {ECO:0000305};
DE AltName: Full=Heat shock protein cognate 72;
DE Flags: Precursor;
GN Name=Hsc70-3 {ECO:0000312|FlyBase:FBgn0001218}; Synonyms=Hsc3;
GN ORFNames=CG4147;
OS Drosophila melanogaster (Fruit fly).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota;
OC Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea;
OC Drosophilidae; Drosophila; Sophophora.
OX NCBI_TaxID=7227;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Larva;
RX PubMed=8514184; DOI=10.1016/0378-1119(93)90558-k;
RA Rubin D.M., Mehta A., Zhu J., Shoham S., Chen X.J., Wells Q., Palter K.B.;
RT "Genomic structure and sequence analysis of Drosophila melanogaster HSC70
RT genes.";
RL Gene 128:155-163(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Berkeley;
RX PubMed=10731132; DOI=10.1126/science.287.5461.2185;
RA Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D.,
RA Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F.,
RA George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N.,
RA Sutton G.G., Wortman J.R., Yandell M.D., Zhang Q., Chen L.X., Brandon R.C.,
RA Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C.,
RA Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A.,
RA An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A.,
RA Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V.,
RA Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J.,
RA Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E.,
RA Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B.,
RA Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I.,
RA Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C.,
RA Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S.,
RA Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M.,
RA Glasser K., Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M.,
RA Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., Hostin D.,
RA Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F.,
RA Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D.,
RA Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A.,
RA Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C.,
RA McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C.,
RA Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L.,
RA Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R.,
RA Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V.,
RA Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F.,
RA Shen H., Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J.,
RA Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., Svirskas R.,
RA Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y.,
RA Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T.,
RA Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S.,
RA Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W.,
RA Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M.,
RA Venter J.C.;
RT "The genome sequence of Drosophila melanogaster.";
RL Science 287:2185-2195(2000).
RN [3]
RP GENOME REANNOTATION.
RC STRAIN=Berkeley;
RX PubMed=12537572; DOI=10.1186/gb-2002-3-12-research0083;
RA Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S.,
RA Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E.,
RA Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P.,
RA Bettencourt B.R., Celniker S.E., de Grey A.D.N.J., Drysdale R.A.,
RA Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., Stapleton M.,
RA Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E.;
RT "Annotation of the Drosophila melanogaster euchromatic genome: a systematic
RT review.";
RL Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Berkeley; TISSUE=Head;
RA Stapleton M., Brokstein P., Hong L., Agbayani A., Carlson J.W., Champe M.,
RA Chavez C., Dorsett V., Dresnek D., Farfan D., Frise E., George R.A.,
RA Gonzalez M., Guarin H., Kronmiller B., Li P.W., Liao G., Miranda A.,
RA Mungall C.J., Nunoo J., Pacleb J.M., Paragas V., Park S., Patel S.,
RA Phouanenavong S., Wan K.H., Yu C., Lewis S.E., Rubin G.M., Celniker S.E.;
RL Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP AMPYLATION.
RX PubMed=25395623; DOI=10.1074/jbc.m114.612515;
RA Ham H., Woolery A.R., Tracy C., Stenesen D., Kraemer H., Orth K.;
RT "Unfolded protein response-regulated Drosophila Fic (dFic) protein
RT reversibly AMPylates BiP chaperone during endoplasmic reticulum
RT homeostasis.";
RL J. Biol. Chem. 289:36059-36069(2014).
RN [6]
RP AMPYLATION AT THR-518, AND DEAMPYLATION AT THR-518.
RX PubMed=29089387; DOI=10.1074/jbc.m117.799296;
RA Casey A.K., Moehlman A.T., Zhang J., Servage K.A., Kraemer H., Orth K.;
RT "Fic-mediated deAMPylation is not dependent on homodimerization and rescues
RT toxic AMPylation in flies.";
RL J. Biol. Chem. 292:21193-21204(2017).
CC -!- FUNCTION: Endoplasmic reticulum chaperone that plays a key role in
CC protein folding and quality control in the endoplasmic reticulum lumen.
CC Involved in the correct folding of proteins and degradation of
CC misfolded proteins (By similarity). Acts as a key repressor of the
CC unfolded protein response (UPR) (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:P11021};
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. In the ADP-bound and nucleotide-free (apo)
CC states, the two domains have little interaction. In contrast, in the
CC ATP-bound state the two domains are tightly coupled, which results in
CC drastically accelerated kinetics in both binding and release of
CC polypeptide substrates. J domain-containing co-chaperones stimulate the
CC ATPase activity and are required for efficient substrate recognition by
CC HSPA5/BiP. {ECO:0000250|UniProtKB:P11021}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
CC {ECO:0000250|UniProtKB:P11021}.
CC -!- PTM: AMPylation at Thr-518 by Fic inactivates the chaperome activity
CC (PubMed:25395623, PubMed:29089387). In response to endoplasmic
CC reticulum stress, de-AMPylation by the same protein, Fic, restores the
CC chaperone activity (PubMed:29089387). {ECO:0000269|PubMed:25395623,
CC ECO:0000269|PubMed:29089387}.
CC -!- SIMILARITY: Belongs to the heat shock protein 70 family. {ECO:0000305}.
CC -!- CAUTION: Was initially thought to be AMPylated at 'Thr-366' by Fic
CC (PubMed:25395623). However, it was later shown to be AMPylated at 'Thr-
CC 518'. {ECO:0000269|PubMed:25395623, ECO:0000269|PubMed:29089387}.
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DR EMBL; L01498; AAA28626.1; -; mRNA.
DR EMBL; AE014298; AAF48095.1; -; Genomic_DNA.
DR EMBL; AE014298; AAN09299.1; -; Genomic_DNA.
DR EMBL; AE014298; AAN09300.1; -; Genomic_DNA.
DR EMBL; AE014298; AAN09301.1; -; Genomic_DNA.
DR EMBL; BT004838; AAO45194.1; -; mRNA.
DR PIR; JN0666; JN0666.
DR RefSeq; NP_001285139.1; NM_001298210.1.
DR RefSeq; NP_511132.2; NM_078577.3.
DR RefSeq; NP_727563.1; NM_167306.2.
DR RefSeq; NP_727564.1; NM_167307.2.
DR RefSeq; NP_727565.1; NM_167308.2.
DR AlphaFoldDB; P29844; -.
DR SMR; P29844; -.
DR BioGRID; 58539; 52.
DR DIP; DIP-19696N; -.
DR IntAct; P29844; 3.
DR MINT; P29844; -.
DR STRING; 7227.FBpp0073445; -.
DR PaxDb; P29844; -.
DR PRIDE; P29844; -.
DR DNASU; 32133; -.
DR EnsemblMetazoa; FBtr0073608; FBpp0073445; FBgn0001218.
DR EnsemblMetazoa; FBtr0073609; FBpp0073446; FBgn0001218.
DR EnsemblMetazoa; FBtr0073610; FBpp0073447; FBgn0001218.
DR EnsemblMetazoa; FBtr0073611; FBpp0073448; FBgn0001218.
DR EnsemblMetazoa; FBtr0345166; FBpp0311376; FBgn0001218.
DR GeneID; 32133; -.
DR KEGG; dme:Dmel_CG4147; -.
DR UCSC; CG4147-RB; d. melanogaster.
DR CTD; 32133; -.
DR FlyBase; FBgn0001218; Hsc70-3.
DR VEuPathDB; VectorBase:FBgn0001218; -.
DR eggNOG; KOG0100; Eukaryota.
DR GeneTree; ENSGT00940000154787; -.
DR HOGENOM; CLU_005965_3_0_1; -.
DR InParanoid; P29844; -.
DR OMA; AYTKNQD; -.
DR OrthoDB; 288077at2759; -.
DR PhylomeDB; P29844; -.
DR Reactome; R-DME-3371453; Regulation of HSF1-mediated heat shock response.
DR SignaLink; P29844; -.
DR BioGRID-ORCS; 32133; 2 hits in 3 CRISPR screens.
DR ChiTaRS; Hsc70-3; fly.
DR GenomeRNAi; 32133; -.
DR PRO; PR:P29844; -.
DR Proteomes; UP000000803; Chromosome X.
DR Bgee; FBgn0001218; Expressed in embryonic/larval hemocyte (Drosophila) and 21 other tissues.
DR ExpressionAtlas; P29844; baseline and differential.
DR Genevisible; P29844; DM.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0012505; C:endomembrane system; HDA:FlyBase.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:FlyBase.
DR GO; GO:0034663; C:endoplasmic reticulum chaperone complex; IPI:FlyBase.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; IBA:GO_Central.
DR GO; GO:0005615; C:extracellular space; IDA:FlyBase.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0005524; F:ATP binding; IBA:GO_Central.
DR GO; GO:0016887; F:ATP hydrolysis activity; IBA:GO_Central.
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:0044183; F:protein folding chaperone; IBA:GO_Central.
DR GO; GO:0051082; F:unfolded protein binding; IBA:GO_Central.
DR GO; GO:0034620; P:cellular response to unfolded protein; IBA:GO_Central.
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:0036335; P:intestinal stem cell homeostasis; IMP:FlyBase.
DR GO; GO:0035194; P:post-transcriptional gene silencing by RNA; IMP:FlyBase.
DR GO; GO:0042026; P:protein refolding; IBA:GO_Central.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IMP:FlyBase.
DR GO; GO:0030431; P:sleep; TAS:FlyBase.
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 1: Evidence at protein level;
KW ATP-binding; Chaperone; Endoplasmic reticulum; Hydrolase;
KW Nucleotide-binding; Phosphoprotein; Reference proteome; Signal.
FT SIGNAL 1..18
FT /evidence="ECO:0000255"
FT CHAIN 19..656
FT /note="Endoplasmic reticulum chaperone BiP"
FT /id="PRO_0000013546"
FT REGION 126..280
FT /note="Nucleotide-binding (NBD)"
FT /evidence="ECO:0000250|UniProtKB:P11021"
FT REGION 420..500
FT /note="Substrate-binding (SBD)"
FT /evidence="ECO:0000250|UniProtKB:P11021"
FT REGION 634..656
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 653..656
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 227..229
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P11021"
FT BINDING 293..300
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P11021"
FT BINDING 364..367
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P11021"
FT MOD_RES 518
FT /note="O-AMP-threonine"
FT /evidence="ECO:0000269|PubMed:25395623,
FT ECO:0000269|PubMed:29089387"
FT CONFLICT 313
FT /note="Missing (in Ref. 4; AAO45194)"
FT /evidence="ECO:0000305"
FT CONFLICT 507
FT /note="G -> A (in Ref. 1; AAA28626)"
FT /evidence="ECO:0000305"
FT CONFLICT 510
FT /note="Q -> T (in Ref. 1; AAA28626)"
FT /evidence="ECO:0000305"
FT CONFLICT 592
FT /note="N -> T (in Ref. 1; AAA28626)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 656 AA; 72261 MW; 06A68F839A06337D CRC64;
MKLCILLAVV AFVGLSLGEE KKEKDKELGT VIGIDLGTTY SCVGVYKNGR VEIIANDQGN
RITPSYVAFT ADGERLIGDA AKNQLTTNPE NTVFDAKRLI GREWSDTNVQ HDIKFFPFKV
VEKNSKPHIS VDTSQGAKVF APEEISAMVL GKMKETAEAY LGKKVTHAVV TVPAYFNDAQ
RQATKDAGVI AGLQVMRIIN EPTAAAIAYG LDKKEGEKNV LVFDLGGGTF DVSLLTIDNG
VFEVVATNGD THLGGEDFDQ RVMDHFIKLY KKKKGKDIRK DNRAVQKLRR EVEKAKRALS
GSHQVRIEIE SFFEGDDFSE TLTRAKFEEL NLDLFRSTLK PVQKVLEDAD MNKKDVHEIV
LVGGSTRIPK VQQLVKDFFG GKEPSRGINP DEAVAYGAAV QAGVLSGEQD TDAIVLLDVN
PLTMGIETVG GVMTKLIPRN TVIPTKKSQV FSTASDNQHT VTIQVYEGER PMTKDNHLLG
KFDLTGIPPA PRGIPQIEVS FEIDANGILQ VSAEDKGTGN KEKIVITNDQ NRLTPEDIDR
MIRDAEKFAD EDKKLKERVE SRNELESYAY SLKNQIGDKD KLGAKLSDDE KNKLESAIDE
SIKWLEQNPD ADPEEYKKQK KDLEAIVQPV IAKLYQGAGG APPPEGGDDA DLKDEL
