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   27-MAR-2024, entry version 180.
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; 53.
DR   DIP; DIP-19696N; -.
DR   IntAct; P29844; 3.
DR   MINT; P29844; -.
DR   STRING; 7227.FBpp0073447; -.
DR   GlyGen; P29844; 1 site, 1 O-linked glycan (1 site).
DR   PaxDb; 7227-FBpp0073445; -.
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   AGR; FB:FBgn0001218; -.
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; 143at2759; -.
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 cell types or tissues.
DR   ExpressionAtlas; P29844; baseline and differential.
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; IEA:UniProtKB-KW.
DR   GO; GO:0016887; F:ATP hydrolysis activity; IDA:FlyBase.
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:0044183; F:protein folding chaperone; IBA:GO_Central.
DR   GO; GO:0015450; F:protein-transporting ATPase activity; ISS:FlyBase.
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:0046621; P:negative regulation of organ growth; IMP:FlyBase.
DR   GO; GO:0035332; P:positive regulation of hippo signaling; IMP:FlyBase.
DR   GO; GO:0042026; P:protein refolding; IBA:GO_Central.
DR   GO; GO:0035194; P:regulatory ncRNA-mediated post-transcriptional gene silencing; IMP:FlyBase.
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; 3.30.420.40; -; 2.
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:SF144; ENDOPLASMIC RETICULUM CHAPERONE BIP; 1.
DR   PANTHER; PTHR19375; HEAT SHOCK PROTEIN 70KDA; 1.
DR   Pfam; PF00012; HSP70; 1.
DR   PRINTS; PR00301; HEATSHOCK70.
DR   SUPFAM; SSF53067; Actin-like ATPase domain; 2.
DR   SUPFAM; SSF100934; Heat shock protein 70kD (HSP70), C-terminal subdomain; 1.
DR   SUPFAM; SSF100920; Heat shock protein 70kD (HSP70), peptide-binding domain; 1.
DR   PROSITE; PS00014; ER_TARGET; 1.
DR   PROSITE; PS00297; HSP70_1; 1.
DR   PROSITE; PS00329; HSP70_2; 1.
DR   PROSITE; PS01036; HSP70_3; 1.
DR   Genevisible; P29844; DM.
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
//