Full text data of HSPA5
HSPA5
(GRP78)
[Confidence: high (present in two of the MS resources)]
78 kDa glucose-regulated protein; GRP-78 (Endoplasmic reticulum lumenal Ca(2+)-binding protein grp78; Heat shock 70 kDa protein 5; Immunoglobulin heavy chain-binding protein; BiP; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
78 kDa glucose-regulated protein; GRP-78 (Endoplasmic reticulum lumenal Ca(2+)-binding protein grp78; Heat shock 70 kDa protein 5; Immunoglobulin heavy chain-binding protein; BiP; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00003362
IPI00003362 78 kDa glucose-regulated protein precursor 78 kDa glucose-regulated protein precursor membrane n/a 3 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 1 3 4 4 ER membrane n/a expected molecular weight found in band between 98 and 188 kDa
IPI00003362 78 kDa glucose-regulated protein precursor 78 kDa glucose-regulated protein precursor membrane n/a 3 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 1 3 4 4 ER membrane n/a expected molecular weight found in band between 98 and 188 kDa
UniProt
P11021
ID GRP78_HUMAN Reviewed; 654 AA.
AC P11021; B0QZ61; Q2EF78; Q9NPF1; Q9UK02;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
read moreDT 11-JUL-2001, sequence version 2.
DT 22-JAN-2014, entry version 164.
DE RecName: Full=78 kDa glucose-regulated protein;
DE Short=GRP-78;
DE AltName: Full=Endoplasmic reticulum lumenal Ca(2+)-binding protein grp78;
DE AltName: Full=Heat shock 70 kDa protein 5;
DE AltName: Full=Immunoglobulin heavy chain-binding protein;
DE Short=BiP;
DE Flags: Precursor;
GN Name=HSPA5; Synonyms=GRP78;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2840249;
RA Ting J., Lee A.S.;
RT "Human gene encoding the 78,000-dalton glucose-regulated protein and
RT its pseudogene: structure, conservation, and regulation.";
RL DNA 7:275-286(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Cervix carcinoma;
RA Chao C.C.K.;
RL Submitted (DEC-1995) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Fibroblast;
RA Hansen J.J., Nielsen M.N., Jorgensen M.M., Gregersen N., Bolund L.;
RT "Grp78 is involved in the quality control of the LDL-receptor.";
RL Submitted (JAN-2000) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Bermudez-Fajardo A., Llewellyn D.H., Campbell A.K., Errington R.R.;
RT "Sequence differences between human grp78/BiP isolated from HeLa cells
RT and previously reported human sequences.";
RL Submitted (DEC-1999) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT HIS-543.
RG NIEHS SNPs program;
RL Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-25.
RX PubMed=1480470; DOI=10.1093/nar/20.24.6481;
RA Chao C.C.K., Lin-Chao S.;
RT "A direct-repeat sequence of the human BiP gene is required for
RT A23187-mediated inducibility and an inducible nuclear factor
RT binding.";
RL Nucleic Acids Res. 20:6481-6485(1992).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 20-650, AND DISEASE.
RC TISSUE=Articular cartilage;
RX PubMed=11160188;
RA Corrigall V.M., Bodman-Smith M.D., Fife M.S., Canas B., Myers L.K.,
RA Wooley P., Soh C., Staines N.A., Pappin D.J.C., Berlo S.E.,
RA van Eden W., van Der Zee R., Lanchbury J.S., Panayi G.S.;
RT "The human endoplasmic reticulum molecular chaperone BiP is an
RT autoantigen for rheumatoid arthritis and prevents the induction of
RT experimental arthritis.";
RL J. Immunol. 166:1492-1498(2001).
RN [11]
RP PROTEIN SEQUENCE OF 22-38.
RC TISSUE=Mammary carcinoma;
RX PubMed=9150946; DOI=10.1002/elps.1150180342;
RA Rasmussen R.K., Ji H., Eddes J.S., Moritz R.L., Reid G.E.,
RA Simpson R.J., Dorow D.S.;
RT "Two-dimensional electrophoretic analysis of human breast carcinoma
RT proteins: mapping of proteins that bind to the SH3 domain of mixed
RT lineage kinase MLK2.";
RL Electrophoresis 18:588-598(1997).
RN [12]
RP PROTEIN SEQUENCE OF 19-39, AND FUNCTION.
RX PubMed=2294010;
RA Dana R.C., Welch W.J., Deftos L.J.;
RT "Heat shock proteins bind calcitonin.";
RL Endocrinology 126:672-674(1990).
RN [13]
RP PROTEIN SEQUENCE OF 19-40.
RC TISSUE=Colon carcinoma;
RX PubMed=9150948; DOI=10.1002/elps.1150180344;
RA Ji H., Reid G.E., Moritz R.L., Eddes J.S., Burgess A.W., Simpson R.J.;
RT "A two-dimensional gel database of human colon carcinoma proteins.";
RL Electrophoresis 18:605-613(1997).
RN [14]
RP PROTEIN SEQUENCE OF 61-74; 82-96; 102-113; 124-152; 164-181; 186-214;
RP 307-336; 353-367; 448-464; 475-492; 563-573; 602-617 AND 622-654, AND
RP MASS SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Vishwanath V., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [15]
RP PROTEIN SEQUENCE OF 582-596, INTERACTION WITH METTL23, METHYLATION AT
RP LYS-585, MUTAGENESIS OF LYS-585, AND MASS SPECTROMETRY.
RX PubMed=23349634; DOI=10.1371/journal.pgen.1003210;
RA Cloutier P., Lavallee-Adam M., Faubert D., Blanchette M., Coulombe B.;
RT "A newly uncovered group of distantly related lysine
RT methyltransferases preferentially interact with molecular chaperones
RT to regulate their activity.";
RL PLoS Genet. 9:E1003210-E1003210(2013).
RN [16]
RP COMPONENT OF A CHAPERONE COMPLEX.
RX PubMed=12475965; DOI=10.1091/mbc.E02-05-0311;
RA Meunier L., Usherwood Y.-K., Chung K.T., Hendershot L.M.;
RT "A subset of chaperones and folding enzymes form multiprotein
RT complexes in endoplasmic reticulum to bind nascent proteins.";
RL Mol. Biol. Cell 13:4456-4469(2002).
RN [17]
RP INTERACTION WITH TRIM21.
RX PubMed=12699405; DOI=10.1046/j.1365-2249.2003.02153.x;
RA Purcell A.W., Todd A., Kinoshita G., Lynch T.A., Keech C.L.,
RA Gething M.J., Gordon T.P.;
RT "Association of stress proteins with autoantigens: a possible
RT mechanism for triggering autoimmunity?";
RL Clin. Exp. Immunol. 132:193-200(2003).
RN [18]
RP INTERACTION WITH DNAJC10.
RX PubMed=12411443; DOI=10.1074/jbc.M206995200;
RA Cunnea P.M., Miranda-Vizuete A., Bertoli G., Simmen T.,
RA Damdimopoulos A.E., Hermann S., Leinonen S., Huikko M.P.,
RA Gustafsson J.-A., Sitia R., Spyrou G.;
RT "ERdj5, an endoplasmic reticulum (ER)-resident protein containing DnaJ
RT and thioredoxin domains, is expressed in secretory cells or following
RT ER stress.";
RL J. Biol. Chem. 278:1059-1066(2003).
RN [19]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=12643545; DOI=10.1021/pr025562r;
RA Basrur V., Yang F., Kushimoto T., Higashimoto Y., Yasumoto K.,
RA Valencia J., Muller J., Vieira W.D., Watabe H., Shabanowitz J.,
RA Hearing V.J., Hunt D.F., Appella E.;
RT "Proteomic analysis of early melanosomes: identification of novel
RT melanosomal proteins.";
RL J. Proteome Res. 2:69-79(2003).
RN [20]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [21]
RP INTERACTION WITH ERLEC1; OS9; SEL1L AND SYVN1.
RX PubMed=18502753; DOI=10.1074/jbc.M709336200;
RA Hosokawa N., Wada I., Nagasawa K., Moriyama T., Okawa K., Nagata K.;
RT "Human XTP3-B forms an endoplasmic reticulum quality control scaffold
RT with the HRD1-SEL1L ubiquitin ligase complex and BiP.";
RL J. Biol. Chem. 283:20914-20924(2008).
RN [22]
RP INTERACTION WITH ERLEC1; OS9; SEL1L AND SYVN1.
RX PubMed=18264092; DOI=10.1038/ncb1689;
RA Christianson J.C., Shaler T.A., Tyler R.E., Kopito R.R.;
RT "OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L
RT ubiquitin ligase complex for ERAD.";
RL Nat. Cell Biol. 10:272-282(2008).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-518, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [25]
RP METHYLATION AT LYS-585, AND MUTAGENESIS OF LYS-585.
RX PubMed=23921388; DOI=10.1074/jbc.M113.483248;
RA Jakobsson M.E., Moen A., Bousset L., Egge-Jacobsen W., Kernstock S.,
RA Melki R., Falnes P.O.;
RT "Identification and characterization of a novel human
RT methyltransferase modulating Hsp70 function through lysine
RT methylation.";
RL J. Biol. Chem. 288:27752-27763(2013).
RN [26]
RP FUNCTION, AND INTERACTION WITH DNAJC10.
RX PubMed=23769672; DOI=10.1016/j.molcel.2013.05.014;
RA Oka O.B., Pringle M.A., Schopp I.M., Braakman I., Bulleid N.J.;
RT "ERdj5 is the ER reductase that catalyzes the removal of non-native
RT disulfides and correct folding of the LDL receptor.";
RL Mol. Cell 50:793-804(2013).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 26-410.
RX PubMed=20072699; DOI=10.1371/journal.pone.0008625;
RA Wisniewska M., Karlberg T., Lehtio L., Johansson I., Kotenyova T.,
RA Moche M., Schuler H.;
RT "Crystal structures of the ATPase domains of four human Hsp70
RT isoforms: HSPA1L/Hsp70-hom, HSPA2/Hsp70-2, HSPA6/Hsp70B', and
RT HSPA5/BiP/GRP78.";
RL PLoS ONE 5:E8625-E8625(2010).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 26-407 IN COMPLEXES WITH ATP
RP ANALOG.
RX PubMed=21526763; DOI=10.1021/jm101625x;
RA Macias A.T., Williamson D.S., Allen N., Borgognoni J., Clay A.,
RA Daniels Z., Dokurno P., Drysdale M.J., Francis G.L., Graham C.J.,
RA Howes R., Matassova N., Murray J.B., Parsons R., Shaw T.,
RA Surgenor A.E., Terry L., Wang Y., Wood M., Massey A.J.;
RT "Adenosine-derived inhibitors of 78 kDa glucose regulated protein
RT (Grp78) ATPase: insights into isoform selectivity.";
RL J. Med. Chem. 54:4034-4041(2011).
CC -!- FUNCTION: Probably plays a role in facilitating the assembly of
CC multimeric protein complexes inside the endoplasmic reticulum.
CC Involved in the correct folding of proteins and degradation of
CC misfolded proteins via its interaction with DNAJC10, probably to
CC facilitate the release of DNAJC10 from its substrate.
CC -!- SUBUNIT: Interacts with DNAJC1 (via J domain) (By similarity).
CC Component of an EIF2 complex at least composed of CELF1/CUGBP1,
CC CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5. Part of a large
CC chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5,
CC HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGT1A1 and very small
CC amounts of ERP29, but not, or at very low levels, CALR nor CANX.
CC Interacts with TMEM132A and TRIM21. May form a complex with
CC ERLEC1, OS9, SEL1L and SYVN1. Interacts with DNAJC10 and MX1.
CC Interacts with METTL23.
CC -!- INTERACTION:
CC Q6T424:-; NbExp=3; IntAct=EBI-354921, EBI-7888150;
CC Q6E0U4:DMKN; NbExp=3; IntAct=EBI-354921, EBI-7943171;
CC Q9UBS4:DNAJB11; NbExp=2; IntAct=EBI-354921, EBI-713113;
CC Q91YW3:Dnajc3 (xeno); NbExp=2; IntAct=EBI-354921, EBI-8381770;
CC Q96IZ0:PAWR; NbExp=8; IntAct=EBI-354921, EBI-595869;
CC Q62627:Pawr (xeno); NbExp=4; IntAct=EBI-354921, EBI-1187240;
CC P04049:RAF1; NbExp=4; IntAct=EBI-354921, EBI-365996;
CC P61619:SEC61A1; NbExp=3; IntAct=EBI-354921, EBI-358919;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. Melanosome.
CC Cytoplasm (By similarity). Note=Identified by mass spectrometry in
CC melanosome fractions from stage I to stage IV.
CC -!- DISEASE: Note=Autoantigen in rheumatoid arthritis.
CC -!- SIMILARITY: Belongs to the heat shock protein 70 family.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/hspa5/";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/HSPA5ID40876ch9q33.html";
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DR EMBL; M19645; AAA52614.1; -; Genomic_DNA.
DR EMBL; X87949; CAA61201.1; -; mRNA.
DR EMBL; AJ271729; CAB71335.1; -; mRNA.
DR EMBL; AF216292; AAF42836.1; -; mRNA.
DR EMBL; DQ385847; ABD04090.1; -; Genomic_DNA.
DR EMBL; AL354710; CAQ08732.1; -; Genomic_DNA.
DR EMBL; CH471090; EAW87620.1; -; Genomic_DNA.
DR EMBL; BC020235; AAH20235.1; -; mRNA.
DR EMBL; X59969; CAA42595.1; -; Genomic_DNA.
DR EMBL; AF188611; AAF13605.1; ALT_SEQ; mRNA.
DR PIR; A29821; A29821.
DR RefSeq; NP_005338.1; NM_005347.4.
DR UniGene; Hs.743241; -.
DR PDB; 3IUC; X-ray; 2.40 A; A/C=26-410.
DR PDB; 3LDL; X-ray; 2.30 A; A/B=26-407.
DR PDB; 3LDN; X-ray; 2.20 A; A/B=26-407.
DR PDB; 3LDO; X-ray; 1.95 A; A/B=26-407.
DR PDB; 3LDP; X-ray; 2.20 A; A/B=26-407.
DR PDBsum; 3IUC; -.
DR PDBsum; 3LDL; -.
DR PDBsum; 3LDN; -.
DR PDBsum; 3LDO; -.
DR PDBsum; 3LDP; -.
DR ProteinModelPortal; P11021; -.
DR SMR; P11021; 26-637.
DR DIP; DIP-33189N; -.
DR IntAct; P11021; 98.
DR MINT; MINT-1135308; -.
DR STRING; 9606.ENSP00000324173; -.
DR BindingDB; P11021; -.
DR ChEMBL; CHEMBL1781865; -.
DR DrugBank; DB00025; Antihemophilic Factor.
DR PhosphoSite; P11021; -.
DR DMDM; 14916999; -.
DR DOSAC-COBS-2DPAGE; P11021; -.
DR OGP; P11021; -.
DR REPRODUCTION-2DPAGE; P11021; -.
DR SWISS-2DPAGE; P11021; -.
DR UCD-2DPAGE; P11021; -.
DR PaxDb; P11021; -.
DR PRIDE; P11021; -.
DR DNASU; 3309; -.
DR Ensembl; ENST00000324460; ENSP00000324173; ENSG00000044574.
DR GeneID; 3309; -.
DR KEGG; hsa:3309; -.
DR UCSC; uc004bpn.3; human.
DR CTD; 3309; -.
DR GeneCards; GC09M127997; -.
DR HGNC; HGNC:5238; HSPA5.
DR HPA; CAB005221; -.
DR HPA; HPA038845; -.
DR HPA; HPA038846; -.
DR MIM; 138120; gene.
DR neXtProt; NX_P11021; -.
DR PharmGKB; PA29504; -.
DR eggNOG; COG0443; -.
DR HOGENOM; HOG000228135; -.
DR HOVERGEN; HBG051845; -.
DR InParanoid; P11021; -.
DR KO; K09490; -.
DR OMA; DKRAVQK; -.
DR OrthoDB; EOG780RKX; -.
DR PhylomeDB; P11021; -.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; HSPA5; human.
DR EvolutionaryTrace; P11021; -.
DR GeneWiki; Binding_immunoglobulin_protein; -.
DR GenomeRNAi; 3309; -.
DR NextBio; 13123; -.
DR PRO; PR:P11021; -.
DR Bgee; P11021; -.
DR CleanEx; HS_HSPA5; -.
DR Genevestigator; P11021; -.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0034663; C:endoplasmic reticulum chaperone complex; IDA:UniProtKB.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; IDA:UniProtKB.
DR GO; GO:0030176; C:integral to endoplasmic reticulum membrane; IDA:BHF-UCL.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0030496; C:midbody; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IMP:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0016887; F:ATPase activity; ISS:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; TAS:UniProtKB.
DR GO; GO:0051087; F:chaperone binding; TAS:BHF-UCL.
DR GO; GO:0051787; F:misfolded protein binding; IDA:UniProtKB.
DR GO; GO:0030674; F:protein binding, bridging; NAS:UniProtKB.
DR GO; GO:0043022; F:ribosome binding; IEA:Ensembl.
DR GO; GO:0051082; F:unfolded protein binding; TAS:UniProtKB.
DR GO; GO:0006987; P:activation of signaling protein activity involved in unfolded protein response; TAS:Reactome.
DR GO; GO:0042149; P:cellular response to glucose starvation; IDA:UniProtKB.
DR GO; GO:0071353; P:cellular response to interleukin-4; IEA:Ensembl.
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:0006983; P:ER overload response; IEA:Ensembl.
DR GO; GO:0030433; P:ER-associated ubiquitin-dependent protein catabolic process; TAS:BHF-UCL.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IEA:Ensembl.
DR GO; GO:0060904; P:regulation of protein folding in endoplasmic reticulum; TAS:BHF-UCL.
DR InterPro; IPR018181; Heat_shock_70_CS.
DR InterPro; IPR013126; Hsp_70_fam.
DR Pfam; PF00012; HSP70; 1.
DR PRINTS; PR00301; HEATSHOCK70.
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 3D-structure; ATP-binding; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Endoplasmic reticulum; Methylation;
KW Nitration; Nucleotide-binding; Phosphoprotein; Polymorphism;
KW Reference proteome; Signal.
FT SIGNAL 1 18
FT CHAIN 19 654 78 kDa glucose-regulated protein.
FT /FTId=PRO_0000013566.
FT NP_BIND 36 39 ATP.
FT NP_BIND 227 229 ATP.
FT NP_BIND 293 300 ATP.
FT NP_BIND 364 367 ATP.
FT MOTIF 651 654 Prevents secretion from ER.
FT BINDING 96 96 ATP.
FT MOD_RES 160 160 Nitrated tyrosine (By similarity).
FT MOD_RES 518 518 Phosphothreonine.
FT MOD_RES 585 585 N6,N6,N6-trimethyllysine; by METTL21A; in
FT vitro.
FT VARIANT 543 543 N -> H (in dbSNP:rs35356639).
FT /FTId=VAR_025815.
FT MUTAGEN 585 585 K->R: Complete loss of in vitro
FT methylation by METTL21A.
FT CONFLICT 297 297 Missing (in Ref. 1; AAA52614 and 2;
FT CAA61201).
FT CONFLICT 418 418 D -> H (in Ref. 1; AAA52614 and 2;
FT CAA61201).
FT CONFLICT 439 439 R -> S (in Ref. 1; AAA52614 and 2;
FT CAA61201).
FT CONFLICT 447 447 K -> N (in Ref. 1; AAA52614 and 2;
FT CAA61201).
FT STRAND 31 34
FT STRAND 37 46
FT STRAND 49 52
FT STRAND 60 63
FT STRAND 66 68
FT STRAND 74 76
FT HELIX 78 82
FT HELIX 84 86
FT HELIX 88 90
FT STRAND 91 93
FT HELIX 95 97
FT TURN 98 100
FT HELIX 106 114
FT STRAND 116 122
FT STRAND 125 131
FT STRAND 137 140
FT HELIX 142 161
FT STRAND 167 172
FT HELIX 178 190
FT STRAND 194 200
FT HELIX 201 208
FT HELIX 211 213
FT STRAND 215 225
FT STRAND 230 238
FT STRAND 241 250
FT HELIX 255 273
FT HELIX 278 280
FT HELIX 282 298
FT TURN 299 301
FT STRAND 302 313
FT STRAND 316 323
FT HELIX 324 336
FT HELIX 339 348
FT HELIX 353 355
FT STRAND 358 363
FT HELIX 364 367
FT HELIX 369 378
FT TURN 379 381
FT TURN 390 392
FT HELIX 393 406
SQ SEQUENCE 654 AA; 72333 MW; 59B7D8D85BC32A00 CRC64;
MKLSLVAAML LLLSAARAEE EDKKEDVGTV VGIDLGTTYS CVGVFKNGRV EIIANDQGNR
ITPSYVAFTP EGERLIGDAA KNQLTSNPEN TVFDAKRLIG RTWNDPSVQQ DIKFLPFKVV
EKKTKPYIQV DIGGGQTKTF APEEISAMVL TKMKETAEAY LGKKVTHAVV TVPAYFNDAQ
RQATKDAGTI AGLNVMRIIN EPTAAAIAYG LDKREGEKNI LVFDLGGGTF DVSLLTIDNG
VFEVVATNGD THLGGEDFDQ RVMEHFIKLY KKKTGKDVRK DNRAVQKLRR EVEKAKRALS
SQHQARIEIE SFYEGEDFSE TLTRAKFEEL NMDLFRSTMK PVQKVLEDSD LKKSDIDEIV
LVGGSTRIPK IQQLVKEFFN GKEPSRGINP DEAVAYGAAV QAGVLSGDQD TGDLVLLDVC
PLTLGIETVG GVMTKLIPRN TVVPTKKSQI FSTASDNQPT VTIKVYEGER PLTKDNHLLG
TFDLTGIPPA PRGVPQIEVT FEIDVNGILR VTAEDKGTGN KNKITITNDQ NRLTPEEIER
MVNDAEKFAE EDKKLKERID TRNELESYAY SLKNQIGDKE KLGGKLSSED KETMEKAVEE
KIEWLESHQD ADIEDFKAKK KELEEIVQPI ISKLYGSAGP PPTGEEDTAE KDEL
//
ID GRP78_HUMAN Reviewed; 654 AA.
AC P11021; B0QZ61; Q2EF78; Q9NPF1; Q9UK02;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
read moreDT 11-JUL-2001, sequence version 2.
DT 22-JAN-2014, entry version 164.
DE RecName: Full=78 kDa glucose-regulated protein;
DE Short=GRP-78;
DE AltName: Full=Endoplasmic reticulum lumenal Ca(2+)-binding protein grp78;
DE AltName: Full=Heat shock 70 kDa protein 5;
DE AltName: Full=Immunoglobulin heavy chain-binding protein;
DE Short=BiP;
DE Flags: Precursor;
GN Name=HSPA5; Synonyms=GRP78;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2840249;
RA Ting J., Lee A.S.;
RT "Human gene encoding the 78,000-dalton glucose-regulated protein and
RT its pseudogene: structure, conservation, and regulation.";
RL DNA 7:275-286(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Cervix carcinoma;
RA Chao C.C.K.;
RL Submitted (DEC-1995) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Fibroblast;
RA Hansen J.J., Nielsen M.N., Jorgensen M.M., Gregersen N., Bolund L.;
RT "Grp78 is involved in the quality control of the LDL-receptor.";
RL Submitted (JAN-2000) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Bermudez-Fajardo A., Llewellyn D.H., Campbell A.K., Errington R.R.;
RT "Sequence differences between human grp78/BiP isolated from HeLa cells
RT and previously reported human sequences.";
RL Submitted (DEC-1999) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT HIS-543.
RG NIEHS SNPs program;
RL Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-25.
RX PubMed=1480470; DOI=10.1093/nar/20.24.6481;
RA Chao C.C.K., Lin-Chao S.;
RT "A direct-repeat sequence of the human BiP gene is required for
RT A23187-mediated inducibility and an inducible nuclear factor
RT binding.";
RL Nucleic Acids Res. 20:6481-6485(1992).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 20-650, AND DISEASE.
RC TISSUE=Articular cartilage;
RX PubMed=11160188;
RA Corrigall V.M., Bodman-Smith M.D., Fife M.S., Canas B., Myers L.K.,
RA Wooley P., Soh C., Staines N.A., Pappin D.J.C., Berlo S.E.,
RA van Eden W., van Der Zee R., Lanchbury J.S., Panayi G.S.;
RT "The human endoplasmic reticulum molecular chaperone BiP is an
RT autoantigen for rheumatoid arthritis and prevents the induction of
RT experimental arthritis.";
RL J. Immunol. 166:1492-1498(2001).
RN [11]
RP PROTEIN SEQUENCE OF 22-38.
RC TISSUE=Mammary carcinoma;
RX PubMed=9150946; DOI=10.1002/elps.1150180342;
RA Rasmussen R.K., Ji H., Eddes J.S., Moritz R.L., Reid G.E.,
RA Simpson R.J., Dorow D.S.;
RT "Two-dimensional electrophoretic analysis of human breast carcinoma
RT proteins: mapping of proteins that bind to the SH3 domain of mixed
RT lineage kinase MLK2.";
RL Electrophoresis 18:588-598(1997).
RN [12]
RP PROTEIN SEQUENCE OF 19-39, AND FUNCTION.
RX PubMed=2294010;
RA Dana R.C., Welch W.J., Deftos L.J.;
RT "Heat shock proteins bind calcitonin.";
RL Endocrinology 126:672-674(1990).
RN [13]
RP PROTEIN SEQUENCE OF 19-40.
RC TISSUE=Colon carcinoma;
RX PubMed=9150948; DOI=10.1002/elps.1150180344;
RA Ji H., Reid G.E., Moritz R.L., Eddes J.S., Burgess A.W., Simpson R.J.;
RT "A two-dimensional gel database of human colon carcinoma proteins.";
RL Electrophoresis 18:605-613(1997).
RN [14]
RP PROTEIN SEQUENCE OF 61-74; 82-96; 102-113; 124-152; 164-181; 186-214;
RP 307-336; 353-367; 448-464; 475-492; 563-573; 602-617 AND 622-654, AND
RP MASS SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Vishwanath V., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [15]
RP PROTEIN SEQUENCE OF 582-596, INTERACTION WITH METTL23, METHYLATION AT
RP LYS-585, MUTAGENESIS OF LYS-585, AND MASS SPECTROMETRY.
RX PubMed=23349634; DOI=10.1371/journal.pgen.1003210;
RA Cloutier P., Lavallee-Adam M., Faubert D., Blanchette M., Coulombe B.;
RT "A newly uncovered group of distantly related lysine
RT methyltransferases preferentially interact with molecular chaperones
RT to regulate their activity.";
RL PLoS Genet. 9:E1003210-E1003210(2013).
RN [16]
RP COMPONENT OF A CHAPERONE COMPLEX.
RX PubMed=12475965; DOI=10.1091/mbc.E02-05-0311;
RA Meunier L., Usherwood Y.-K., Chung K.T., Hendershot L.M.;
RT "A subset of chaperones and folding enzymes form multiprotein
RT complexes in endoplasmic reticulum to bind nascent proteins.";
RL Mol. Biol. Cell 13:4456-4469(2002).
RN [17]
RP INTERACTION WITH TRIM21.
RX PubMed=12699405; DOI=10.1046/j.1365-2249.2003.02153.x;
RA Purcell A.W., Todd A., Kinoshita G., Lynch T.A., Keech C.L.,
RA Gething M.J., Gordon T.P.;
RT "Association of stress proteins with autoantigens: a possible
RT mechanism for triggering autoimmunity?";
RL Clin. Exp. Immunol. 132:193-200(2003).
RN [18]
RP INTERACTION WITH DNAJC10.
RX PubMed=12411443; DOI=10.1074/jbc.M206995200;
RA Cunnea P.M., Miranda-Vizuete A., Bertoli G., Simmen T.,
RA Damdimopoulos A.E., Hermann S., Leinonen S., Huikko M.P.,
RA Gustafsson J.-A., Sitia R., Spyrou G.;
RT "ERdj5, an endoplasmic reticulum (ER)-resident protein containing DnaJ
RT and thioredoxin domains, is expressed in secretory cells or following
RT ER stress.";
RL J. Biol. Chem. 278:1059-1066(2003).
RN [19]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=12643545; DOI=10.1021/pr025562r;
RA Basrur V., Yang F., Kushimoto T., Higashimoto Y., Yasumoto K.,
RA Valencia J., Muller J., Vieira W.D., Watabe H., Shabanowitz J.,
RA Hearing V.J., Hunt D.F., Appella E.;
RT "Proteomic analysis of early melanosomes: identification of novel
RT melanosomal proteins.";
RL J. Proteome Res. 2:69-79(2003).
RN [20]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [21]
RP INTERACTION WITH ERLEC1; OS9; SEL1L AND SYVN1.
RX PubMed=18502753; DOI=10.1074/jbc.M709336200;
RA Hosokawa N., Wada I., Nagasawa K., Moriyama T., Okawa K., Nagata K.;
RT "Human XTP3-B forms an endoplasmic reticulum quality control scaffold
RT with the HRD1-SEL1L ubiquitin ligase complex and BiP.";
RL J. Biol. Chem. 283:20914-20924(2008).
RN [22]
RP INTERACTION WITH ERLEC1; OS9; SEL1L AND SYVN1.
RX PubMed=18264092; DOI=10.1038/ncb1689;
RA Christianson J.C., Shaler T.A., Tyler R.E., Kopito R.R.;
RT "OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L
RT ubiquitin ligase complex for ERAD.";
RL Nat. Cell Biol. 10:272-282(2008).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-518, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [25]
RP METHYLATION AT LYS-585, AND MUTAGENESIS OF LYS-585.
RX PubMed=23921388; DOI=10.1074/jbc.M113.483248;
RA Jakobsson M.E., Moen A., Bousset L., Egge-Jacobsen W., Kernstock S.,
RA Melki R., Falnes P.O.;
RT "Identification and characterization of a novel human
RT methyltransferase modulating Hsp70 function through lysine
RT methylation.";
RL J. Biol. Chem. 288:27752-27763(2013).
RN [26]
RP FUNCTION, AND INTERACTION WITH DNAJC10.
RX PubMed=23769672; DOI=10.1016/j.molcel.2013.05.014;
RA Oka O.B., Pringle M.A., Schopp I.M., Braakman I., Bulleid N.J.;
RT "ERdj5 is the ER reductase that catalyzes the removal of non-native
RT disulfides and correct folding of the LDL receptor.";
RL Mol. Cell 50:793-804(2013).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 26-410.
RX PubMed=20072699; DOI=10.1371/journal.pone.0008625;
RA Wisniewska M., Karlberg T., Lehtio L., Johansson I., Kotenyova T.,
RA Moche M., Schuler H.;
RT "Crystal structures of the ATPase domains of four human Hsp70
RT isoforms: HSPA1L/Hsp70-hom, HSPA2/Hsp70-2, HSPA6/Hsp70B', and
RT HSPA5/BiP/GRP78.";
RL PLoS ONE 5:E8625-E8625(2010).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 26-407 IN COMPLEXES WITH ATP
RP ANALOG.
RX PubMed=21526763; DOI=10.1021/jm101625x;
RA Macias A.T., Williamson D.S., Allen N., Borgognoni J., Clay A.,
RA Daniels Z., Dokurno P., Drysdale M.J., Francis G.L., Graham C.J.,
RA Howes R., Matassova N., Murray J.B., Parsons R., Shaw T.,
RA Surgenor A.E., Terry L., Wang Y., Wood M., Massey A.J.;
RT "Adenosine-derived inhibitors of 78 kDa glucose regulated protein
RT (Grp78) ATPase: insights into isoform selectivity.";
RL J. Med. Chem. 54:4034-4041(2011).
CC -!- FUNCTION: Probably plays a role in facilitating the assembly of
CC multimeric protein complexes inside the endoplasmic reticulum.
CC Involved in the correct folding of proteins and degradation of
CC misfolded proteins via its interaction with DNAJC10, probably to
CC facilitate the release of DNAJC10 from its substrate.
CC -!- SUBUNIT: Interacts with DNAJC1 (via J domain) (By similarity).
CC Component of an EIF2 complex at least composed of CELF1/CUGBP1,
CC CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5. Part of a large
CC chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5,
CC HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGT1A1 and very small
CC amounts of ERP29, but not, or at very low levels, CALR nor CANX.
CC Interacts with TMEM132A and TRIM21. May form a complex with
CC ERLEC1, OS9, SEL1L and SYVN1. Interacts with DNAJC10 and MX1.
CC Interacts with METTL23.
CC -!- INTERACTION:
CC Q6T424:-; NbExp=3; IntAct=EBI-354921, EBI-7888150;
CC Q6E0U4:DMKN; NbExp=3; IntAct=EBI-354921, EBI-7943171;
CC Q9UBS4:DNAJB11; NbExp=2; IntAct=EBI-354921, EBI-713113;
CC Q91YW3:Dnajc3 (xeno); NbExp=2; IntAct=EBI-354921, EBI-8381770;
CC Q96IZ0:PAWR; NbExp=8; IntAct=EBI-354921, EBI-595869;
CC Q62627:Pawr (xeno); NbExp=4; IntAct=EBI-354921, EBI-1187240;
CC P04049:RAF1; NbExp=4; IntAct=EBI-354921, EBI-365996;
CC P61619:SEC61A1; NbExp=3; IntAct=EBI-354921, EBI-358919;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. Melanosome.
CC Cytoplasm (By similarity). Note=Identified by mass spectrometry in
CC melanosome fractions from stage I to stage IV.
CC -!- DISEASE: Note=Autoantigen in rheumatoid arthritis.
CC -!- SIMILARITY: Belongs to the heat shock protein 70 family.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/hspa5/";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/HSPA5ID40876ch9q33.html";
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DR EMBL; M19645; AAA52614.1; -; Genomic_DNA.
DR EMBL; X87949; CAA61201.1; -; mRNA.
DR EMBL; AJ271729; CAB71335.1; -; mRNA.
DR EMBL; AF216292; AAF42836.1; -; mRNA.
DR EMBL; DQ385847; ABD04090.1; -; Genomic_DNA.
DR EMBL; AL354710; CAQ08732.1; -; Genomic_DNA.
DR EMBL; CH471090; EAW87620.1; -; Genomic_DNA.
DR EMBL; BC020235; AAH20235.1; -; mRNA.
DR EMBL; X59969; CAA42595.1; -; Genomic_DNA.
DR EMBL; AF188611; AAF13605.1; ALT_SEQ; mRNA.
DR PIR; A29821; A29821.
DR RefSeq; NP_005338.1; NM_005347.4.
DR UniGene; Hs.743241; -.
DR PDB; 3IUC; X-ray; 2.40 A; A/C=26-410.
DR PDB; 3LDL; X-ray; 2.30 A; A/B=26-407.
DR PDB; 3LDN; X-ray; 2.20 A; A/B=26-407.
DR PDB; 3LDO; X-ray; 1.95 A; A/B=26-407.
DR PDB; 3LDP; X-ray; 2.20 A; A/B=26-407.
DR PDBsum; 3IUC; -.
DR PDBsum; 3LDL; -.
DR PDBsum; 3LDN; -.
DR PDBsum; 3LDO; -.
DR PDBsum; 3LDP; -.
DR ProteinModelPortal; P11021; -.
DR SMR; P11021; 26-637.
DR DIP; DIP-33189N; -.
DR IntAct; P11021; 98.
DR MINT; MINT-1135308; -.
DR STRING; 9606.ENSP00000324173; -.
DR BindingDB; P11021; -.
DR ChEMBL; CHEMBL1781865; -.
DR DrugBank; DB00025; Antihemophilic Factor.
DR PhosphoSite; P11021; -.
DR DMDM; 14916999; -.
DR DOSAC-COBS-2DPAGE; P11021; -.
DR OGP; P11021; -.
DR REPRODUCTION-2DPAGE; P11021; -.
DR SWISS-2DPAGE; P11021; -.
DR UCD-2DPAGE; P11021; -.
DR PaxDb; P11021; -.
DR PRIDE; P11021; -.
DR DNASU; 3309; -.
DR Ensembl; ENST00000324460; ENSP00000324173; ENSG00000044574.
DR GeneID; 3309; -.
DR KEGG; hsa:3309; -.
DR UCSC; uc004bpn.3; human.
DR CTD; 3309; -.
DR GeneCards; GC09M127997; -.
DR HGNC; HGNC:5238; HSPA5.
DR HPA; CAB005221; -.
DR HPA; HPA038845; -.
DR HPA; HPA038846; -.
DR MIM; 138120; gene.
DR neXtProt; NX_P11021; -.
DR PharmGKB; PA29504; -.
DR eggNOG; COG0443; -.
DR HOGENOM; HOG000228135; -.
DR HOVERGEN; HBG051845; -.
DR InParanoid; P11021; -.
DR KO; K09490; -.
DR OMA; DKRAVQK; -.
DR OrthoDB; EOG780RKX; -.
DR PhylomeDB; P11021; -.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; HSPA5; human.
DR EvolutionaryTrace; P11021; -.
DR GeneWiki; Binding_immunoglobulin_protein; -.
DR GenomeRNAi; 3309; -.
DR NextBio; 13123; -.
DR PRO; PR:P11021; -.
DR Bgee; P11021; -.
DR CleanEx; HS_HSPA5; -.
DR Genevestigator; P11021; -.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0034663; C:endoplasmic reticulum chaperone complex; IDA:UniProtKB.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; IDA:UniProtKB.
DR GO; GO:0030176; C:integral to endoplasmic reticulum membrane; IDA:BHF-UCL.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0030496; C:midbody; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IMP:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0016887; F:ATPase activity; ISS:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; TAS:UniProtKB.
DR GO; GO:0051087; F:chaperone binding; TAS:BHF-UCL.
DR GO; GO:0051787; F:misfolded protein binding; IDA:UniProtKB.
DR GO; GO:0030674; F:protein binding, bridging; NAS:UniProtKB.
DR GO; GO:0043022; F:ribosome binding; IEA:Ensembl.
DR GO; GO:0051082; F:unfolded protein binding; TAS:UniProtKB.
DR GO; GO:0006987; P:activation of signaling protein activity involved in unfolded protein response; TAS:Reactome.
DR GO; GO:0042149; P:cellular response to glucose starvation; IDA:UniProtKB.
DR GO; GO:0071353; P:cellular response to interleukin-4; IEA:Ensembl.
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:0006983; P:ER overload response; IEA:Ensembl.
DR GO; GO:0030433; P:ER-associated ubiquitin-dependent protein catabolic process; TAS:BHF-UCL.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IEA:Ensembl.
DR GO; GO:0060904; P:regulation of protein folding in endoplasmic reticulum; TAS:BHF-UCL.
DR InterPro; IPR018181; Heat_shock_70_CS.
DR InterPro; IPR013126; Hsp_70_fam.
DR Pfam; PF00012; HSP70; 1.
DR PRINTS; PR00301; HEATSHOCK70.
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 3D-structure; ATP-binding; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Endoplasmic reticulum; Methylation;
KW Nitration; Nucleotide-binding; Phosphoprotein; Polymorphism;
KW Reference proteome; Signal.
FT SIGNAL 1 18
FT CHAIN 19 654 78 kDa glucose-regulated protein.
FT /FTId=PRO_0000013566.
FT NP_BIND 36 39 ATP.
FT NP_BIND 227 229 ATP.
FT NP_BIND 293 300 ATP.
FT NP_BIND 364 367 ATP.
FT MOTIF 651 654 Prevents secretion from ER.
FT BINDING 96 96 ATP.
FT MOD_RES 160 160 Nitrated tyrosine (By similarity).
FT MOD_RES 518 518 Phosphothreonine.
FT MOD_RES 585 585 N6,N6,N6-trimethyllysine; by METTL21A; in
FT vitro.
FT VARIANT 543 543 N -> H (in dbSNP:rs35356639).
FT /FTId=VAR_025815.
FT MUTAGEN 585 585 K->R: Complete loss of in vitro
FT methylation by METTL21A.
FT CONFLICT 297 297 Missing (in Ref. 1; AAA52614 and 2;
FT CAA61201).
FT CONFLICT 418 418 D -> H (in Ref. 1; AAA52614 and 2;
FT CAA61201).
FT CONFLICT 439 439 R -> S (in Ref. 1; AAA52614 and 2;
FT CAA61201).
FT CONFLICT 447 447 K -> N (in Ref. 1; AAA52614 and 2;
FT CAA61201).
FT STRAND 31 34
FT STRAND 37 46
FT STRAND 49 52
FT STRAND 60 63
FT STRAND 66 68
FT STRAND 74 76
FT HELIX 78 82
FT HELIX 84 86
FT HELIX 88 90
FT STRAND 91 93
FT HELIX 95 97
FT TURN 98 100
FT HELIX 106 114
FT STRAND 116 122
FT STRAND 125 131
FT STRAND 137 140
FT HELIX 142 161
FT STRAND 167 172
FT HELIX 178 190
FT STRAND 194 200
FT HELIX 201 208
FT HELIX 211 213
FT STRAND 215 225
FT STRAND 230 238
FT STRAND 241 250
FT HELIX 255 273
FT HELIX 278 280
FT HELIX 282 298
FT TURN 299 301
FT STRAND 302 313
FT STRAND 316 323
FT HELIX 324 336
FT HELIX 339 348
FT HELIX 353 355
FT STRAND 358 363
FT HELIX 364 367
FT HELIX 369 378
FT TURN 379 381
FT TURN 390 392
FT HELIX 393 406
SQ SEQUENCE 654 AA; 72333 MW; 59B7D8D85BC32A00 CRC64;
MKLSLVAAML LLLSAARAEE EDKKEDVGTV VGIDLGTTYS CVGVFKNGRV EIIANDQGNR
ITPSYVAFTP EGERLIGDAA KNQLTSNPEN TVFDAKRLIG RTWNDPSVQQ DIKFLPFKVV
EKKTKPYIQV DIGGGQTKTF APEEISAMVL TKMKETAEAY LGKKVTHAVV TVPAYFNDAQ
RQATKDAGTI AGLNVMRIIN EPTAAAIAYG LDKREGEKNI LVFDLGGGTF DVSLLTIDNG
VFEVVATNGD THLGGEDFDQ RVMEHFIKLY KKKTGKDVRK DNRAVQKLRR EVEKAKRALS
SQHQARIEIE SFYEGEDFSE TLTRAKFEEL NMDLFRSTMK PVQKVLEDSD LKKSDIDEIV
LVGGSTRIPK IQQLVKEFFN GKEPSRGINP DEAVAYGAAV QAGVLSGDQD TGDLVLLDVC
PLTLGIETVG GVMTKLIPRN TVVPTKKSQI FSTASDNQPT VTIKVYEGER PLTKDNHLLG
TFDLTGIPPA PRGVPQIEVT FEIDVNGILR VTAEDKGTGN KNKITITNDQ NRLTPEEIER
MVNDAEKFAE EDKKLKERID TRNELESYAY SLKNQIGDKE KLGGKLSSED KETMEKAVEE
KIEWLESHQD ADIEDFKAKK KELEEIVQPI ISKLYGSAGP PPTGEEDTAE KDEL
//
MIM
138120
*RECORD*
*FIELD* NO
138120
*FIELD* TI
*138120 HEAT-SHOCK 70-KD PROTEIN 5; HSPA5
;;GLUCOSE-REGULATED PROTEIN, 78-KD; GRP78;;
read moreIMMUNOGLOBULIN HEAVY CHAIN-BINDING PROTEIN; BIP
*FIELD* TX
DESCRIPTION
When Chinese hamster K12 cells are starved of glucose, the synthesis of
several proteins, called glucose-regulated proteins (GRPs), is markedly
increased. Hendershot et al. (1994) pointed out that one of these, GRP78
(HSPA5), also referred to as 'immunoglobulin heavy chain-binding
protein' (BiP), is a member of the heat-shock protein-70 (HSP70) family
and is involved in the folding and assembly of proteins in the
endoplasmic reticulum (ER). Because so many ER proteins interact
transiently with GRP78, it may play a key role in monitoring protein
transport through the cell.
CLONING
Lee et al. (1981) cloned the hamster Grp78 gene. Ting and Lee (1988)
isolated and characterized the human GRP78 gene. GRP78 is highly
conserved in evolution and is transcriptionally regulated (Lee et al.,
1983; Ting and Lee, 1988).
GENE FUNCTION
To examine how the binding of BiP influences the conformational
maturation of thyroglobulin (TG; 188450), Muresan and Arvan (1998)
expressed TG in Chinese hamster ovary (CHO) cells genetically
manipulated for selectively increased BiP expression (CHO-B cells). The
TG expressed in CHO-B cells did not contain any mutations that induce
misfolding (i.e., no unfolded protein response), so that levels of all
other ER chaperones were normal. Increased availability of BiP did not
accelerate TG secretion; rather, the export of newly synthesized TG was
delayed. TG that was detained intracellularly was concentrated in the
ER. Muresan and Arvan (1998) concluded that increased binding of BiP to
TG leads to its delayed conformational maturation in the ER.
Shen et al. (2002) found that HSPA5 binds ATF6 (605537) and dissociates
from it in response to ER stress. They showed that deletion of luminal
HSPA5 binding sites from ATF6, while retaining a Golgi localization
signal, resulted in constitutive translocation of ATF6 to the Golgi. In
cells overexpressing HSPA5, they observed that translocation of ATF6 to
the Golgi was slowed. Shen et al. (2002) concluded that HSPA5 retains
ATF6 in the ER by inhibiting its Golgi localization signals and that
dissociation of HSPA5 during ER stress allows ATF6 to be transported to
the Golgi. Sommer and Jarosch (2002) summarized the findings of Shen et
al. (2002) in a discussion of the proteins involved in regulating levels
of aberrant proteins within the ER. They suggested that the findings of
Shen et al. (2002) demonstrated that HSPA5 is a key element in sensing
the folding capacity within the ER.
Two members of the HSP70 family are required for protein biogenesis in
the yeast endoplasmic reticulum: Lhs1 (homologous to HYOU1; 601746) and
Kar2 (homologous to HSPA5). Steel et al. (2004) found that Lhs1 and Kar2
specifically interacted to couple, and coordinately regulate, their
respective activities. Lhs1 stimulated Kar2 by providing a specific
nucleotide exchange activity, whereas Kar2 reciprocally activated the
Lhs1 ATPase. In yeast, the 2 ATPase activities are coupled, and their
coordinated regulation is essential for normal function in vivo.
Ushioda et al. (2008) found that the ER-resident protein ERDJ5 (607987)
had a reductase activity, cleaved the disulfide bonds of misfolded
proteins, and accelerated ER-associated degradation (ERAD) through its
physical and functional associations with EDEM (607673) and the
ER-resident chaperone BIP. Thus, Ushioda et al. (2008) concluded that
ERDJ5 is a member of a supramolecular ERAD complex that recognizes and
unfolds misfolded proteins for their efficient retrotranslocation.
Using human cell lines, Mueller et al. (2008) identified several
components of a protein complex required for retrotranslocation or
dislocation of misfolded proteins from the ER lumen to the cytosol for
proteasome-dependent degradation. These included SEL1L (602329), HRD1
(SYVN1; 608046), derlin-2 (DERL2; 610304), the ATPase p97 (VCP; 601023),
PDI (P4HB; 176790), BIP, calnexin (CANX; 114217), AUP1 (602434), UBXD8
(FAF2), UBC6E (UBE2J1), and OS9 (609677).
GENE STRUCTURE
Ting and Lee (1988) determined that the GRP78 gene contains 8 exons and
spans over 5 kb.
MAPPING
Law et al. (1984) used the hamster Grp78 cDNA probe to map the human
gene for GRP78 in hamster-human hybrids. They concluded that the GRP78
gene maps to 9cen-qter. Using PCR amplification of DNA from human/rodent
somatic hybrids in conjunction with fluorescence in situ hybridization,
Hendershot et al. (1994) assigned the GRP78 gene to 9q34.
*FIELD* RF
1. Hendershot, L. M.; Valentine, V. A.; Lee, A. S.; Morris, S. W.;
Shapiro, D. N.: Localization of the gene encoding human BiP/GRP78,
the endoplasmic reticulum cognate of the HSP70 family, to chromosome
9q34. Genomics 20: 281-284, 1994.
2. Law, M. L.; Seeliger, M. B.; Lee, A. S.; Kao, F. T.: Genetic mapping
of the structural gene coding for a glucose-regulated protein (GRP78)
of 78k-dalton to the long arm of human chromosome 9. (Abstract) Cytogenet.
Cell Genet. 37: 518-519, 1984.
3. Lee, A. S.; Delegeane, A.; Scharff, D.: Highly conserved glucose-regulated
protein in hamster and chicken cells: preliminary characterization
of its cDNA clone. Proc. Nat. Acad. Sci. 78: 4922-4925, 1981.
4. Lee, A. S.; Delegeane, A. M.; Baker, V.; Chow, P. C.: Transcriptional
regulation of two genes specifically induced by glucose starvation
in hamster mutant fibroblast cell line. J. Biol. Chem. 258: 597-603,
1983.
5. Mueller, B.; Klemm, E. J.; Spooner, E.; Claessen, J. H.; Ploegh,
H. L.: SEL1L nucleates a protein complex required for dislocation
of misfolded glycoproteins. Proc. Nat. Acad. Sci. 105: 12325-12330,
2008.
6. Muresan, Z.; Arvan, P.: Enhanced binding to the molecular chaperone
BiP slows thyroglobulin export from the endoplasmic reticulum. Molec.
Endocr. 12: 458-467, 1998.
7. Shen, J.; Chen, X.; Hendershot, L.; Prywes, R.: ER stress regulation
of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking
of Golgi localization signals. Dev. Cell 3: 99-111, 2002.
8. Sommer, T.; Jarosch, E.: BiP binding keeps ATF6 at bay. Dev.
Cell 3: 1-2, 2002.
9. Steel, G. J.; Fullerton, D. M.; Tyson, J. R.; Stirling, C. J.:
Coordinated activation of Hsp70 chaperones. Science 303: 98-101,
2004.
10. Ting, J.; Lee, A. S.: Human gene encoding the 78,000-dalton glucose-regulated
protein and its pseudogene: structure, conservation, and regulation. DNA 7:
275-286, 1988.
11. Ushioda, R.; Hoseki, J.; Araki, K.; Jansen, G.; Thomas, D. Y.;
Nagata, K.: ERdj5 is required as a disulfide reductase for degradation
of misfolded proteins in the ER. Science 321: 569-572, 2008.
*FIELD* CN
Patricia A. Hartz - updated: 11/3/2009
Ada Hamosh - updated: 8/27/2008
Dawn Watkins-Chow - updated: 2/26/2003
John A. Phillips, III - updated: 4/13/1999
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
mgross: 11/10/2009
terry: 11/3/2009
alopez: 8/28/2008
terry: 8/27/2008
tkritzer: 1/20/2004
carol: 1/20/2004
tkritzer: 2/26/2003
mgross: 4/16/1999
mgross: 4/13/1999
terry: 7/24/1998
carol: 7/10/1998
carol: 7/8/1998
mark: 4/10/1997
carol: 5/16/1994
mimadm: 4/19/1994
carol: 7/22/1993
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/28/1990
*RECORD*
*FIELD* NO
138120
*FIELD* TI
*138120 HEAT-SHOCK 70-KD PROTEIN 5; HSPA5
;;GLUCOSE-REGULATED PROTEIN, 78-KD; GRP78;;
read moreIMMUNOGLOBULIN HEAVY CHAIN-BINDING PROTEIN; BIP
*FIELD* TX
DESCRIPTION
When Chinese hamster K12 cells are starved of glucose, the synthesis of
several proteins, called glucose-regulated proteins (GRPs), is markedly
increased. Hendershot et al. (1994) pointed out that one of these, GRP78
(HSPA5), also referred to as 'immunoglobulin heavy chain-binding
protein' (BiP), is a member of the heat-shock protein-70 (HSP70) family
and is involved in the folding and assembly of proteins in the
endoplasmic reticulum (ER). Because so many ER proteins interact
transiently with GRP78, it may play a key role in monitoring protein
transport through the cell.
CLONING
Lee et al. (1981) cloned the hamster Grp78 gene. Ting and Lee (1988)
isolated and characterized the human GRP78 gene. GRP78 is highly
conserved in evolution and is transcriptionally regulated (Lee et al.,
1983; Ting and Lee, 1988).
GENE FUNCTION
To examine how the binding of BiP influences the conformational
maturation of thyroglobulin (TG; 188450), Muresan and Arvan (1998)
expressed TG in Chinese hamster ovary (CHO) cells genetically
manipulated for selectively increased BiP expression (CHO-B cells). The
TG expressed in CHO-B cells did not contain any mutations that induce
misfolding (i.e., no unfolded protein response), so that levels of all
other ER chaperones were normal. Increased availability of BiP did not
accelerate TG secretion; rather, the export of newly synthesized TG was
delayed. TG that was detained intracellularly was concentrated in the
ER. Muresan and Arvan (1998) concluded that increased binding of BiP to
TG leads to its delayed conformational maturation in the ER.
Shen et al. (2002) found that HSPA5 binds ATF6 (605537) and dissociates
from it in response to ER stress. They showed that deletion of luminal
HSPA5 binding sites from ATF6, while retaining a Golgi localization
signal, resulted in constitutive translocation of ATF6 to the Golgi. In
cells overexpressing HSPA5, they observed that translocation of ATF6 to
the Golgi was slowed. Shen et al. (2002) concluded that HSPA5 retains
ATF6 in the ER by inhibiting its Golgi localization signals and that
dissociation of HSPA5 during ER stress allows ATF6 to be transported to
the Golgi. Sommer and Jarosch (2002) summarized the findings of Shen et
al. (2002) in a discussion of the proteins involved in regulating levels
of aberrant proteins within the ER. They suggested that the findings of
Shen et al. (2002) demonstrated that HSPA5 is a key element in sensing
the folding capacity within the ER.
Two members of the HSP70 family are required for protein biogenesis in
the yeast endoplasmic reticulum: Lhs1 (homologous to HYOU1; 601746) and
Kar2 (homologous to HSPA5). Steel et al. (2004) found that Lhs1 and Kar2
specifically interacted to couple, and coordinately regulate, their
respective activities. Lhs1 stimulated Kar2 by providing a specific
nucleotide exchange activity, whereas Kar2 reciprocally activated the
Lhs1 ATPase. In yeast, the 2 ATPase activities are coupled, and their
coordinated regulation is essential for normal function in vivo.
Ushioda et al. (2008) found that the ER-resident protein ERDJ5 (607987)
had a reductase activity, cleaved the disulfide bonds of misfolded
proteins, and accelerated ER-associated degradation (ERAD) through its
physical and functional associations with EDEM (607673) and the
ER-resident chaperone BIP. Thus, Ushioda et al. (2008) concluded that
ERDJ5 is a member of a supramolecular ERAD complex that recognizes and
unfolds misfolded proteins for their efficient retrotranslocation.
Using human cell lines, Mueller et al. (2008) identified several
components of a protein complex required for retrotranslocation or
dislocation of misfolded proteins from the ER lumen to the cytosol for
proteasome-dependent degradation. These included SEL1L (602329), HRD1
(SYVN1; 608046), derlin-2 (DERL2; 610304), the ATPase p97 (VCP; 601023),
PDI (P4HB; 176790), BIP, calnexin (CANX; 114217), AUP1 (602434), UBXD8
(FAF2), UBC6E (UBE2J1), and OS9 (609677).
GENE STRUCTURE
Ting and Lee (1988) determined that the GRP78 gene contains 8 exons and
spans over 5 kb.
MAPPING
Law et al. (1984) used the hamster Grp78 cDNA probe to map the human
gene for GRP78 in hamster-human hybrids. They concluded that the GRP78
gene maps to 9cen-qter. Using PCR amplification of DNA from human/rodent
somatic hybrids in conjunction with fluorescence in situ hybridization,
Hendershot et al. (1994) assigned the GRP78 gene to 9q34.
*FIELD* RF
1. Hendershot, L. M.; Valentine, V. A.; Lee, A. S.; Morris, S. W.;
Shapiro, D. N.: Localization of the gene encoding human BiP/GRP78,
the endoplasmic reticulum cognate of the HSP70 family, to chromosome
9q34. Genomics 20: 281-284, 1994.
2. Law, M. L.; Seeliger, M. B.; Lee, A. S.; Kao, F. T.: Genetic mapping
of the structural gene coding for a glucose-regulated protein (GRP78)
of 78k-dalton to the long arm of human chromosome 9. (Abstract) Cytogenet.
Cell Genet. 37: 518-519, 1984.
3. Lee, A. S.; Delegeane, A.; Scharff, D.: Highly conserved glucose-regulated
protein in hamster and chicken cells: preliminary characterization
of its cDNA clone. Proc. Nat. Acad. Sci. 78: 4922-4925, 1981.
4. Lee, A. S.; Delegeane, A. M.; Baker, V.; Chow, P. C.: Transcriptional
regulation of two genes specifically induced by glucose starvation
in hamster mutant fibroblast cell line. J. Biol. Chem. 258: 597-603,
1983.
5. Mueller, B.; Klemm, E. J.; Spooner, E.; Claessen, J. H.; Ploegh,
H. L.: SEL1L nucleates a protein complex required for dislocation
of misfolded glycoproteins. Proc. Nat. Acad. Sci. 105: 12325-12330,
2008.
6. Muresan, Z.; Arvan, P.: Enhanced binding to the molecular chaperone
BiP slows thyroglobulin export from the endoplasmic reticulum. Molec.
Endocr. 12: 458-467, 1998.
7. Shen, J.; Chen, X.; Hendershot, L.; Prywes, R.: ER stress regulation
of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking
of Golgi localization signals. Dev. Cell 3: 99-111, 2002.
8. Sommer, T.; Jarosch, E.: BiP binding keeps ATF6 at bay. Dev.
Cell 3: 1-2, 2002.
9. Steel, G. J.; Fullerton, D. M.; Tyson, J. R.; Stirling, C. J.:
Coordinated activation of Hsp70 chaperones. Science 303: 98-101,
2004.
10. Ting, J.; Lee, A. S.: Human gene encoding the 78,000-dalton glucose-regulated
protein and its pseudogene: structure, conservation, and regulation. DNA 7:
275-286, 1988.
11. Ushioda, R.; Hoseki, J.; Araki, K.; Jansen, G.; Thomas, D. Y.;
Nagata, K.: ERdj5 is required as a disulfide reductase for degradation
of misfolded proteins in the ER. Science 321: 569-572, 2008.
*FIELD* CN
Patricia A. Hartz - updated: 11/3/2009
Ada Hamosh - updated: 8/27/2008
Dawn Watkins-Chow - updated: 2/26/2003
John A. Phillips, III - updated: 4/13/1999
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
mgross: 11/10/2009
terry: 11/3/2009
alopez: 8/28/2008
terry: 8/27/2008
tkritzer: 1/20/2004
carol: 1/20/2004
tkritzer: 2/26/2003
mgross: 4/16/1999
mgross: 4/13/1999
terry: 7/24/1998
carol: 7/10/1998
carol: 7/8/1998
mark: 4/10/1997
carol: 5/16/1994
mimadm: 4/19/1994
carol: 7/22/1993
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/28/1990