Search by BoMiProt ID - Bomi138

Primary Information

BoMiProt ID Bomi138
Protein Name 78 kDa glucose-regulated protein
Organism Bos taurus
Uniprot IDQ0VCX2
Milk FractionWhey
Ref Sequence ID NP_001068616.1
Aminoacid Length 655
Molecular Weight 72400
FASTA Sequence Download
Gene Name HSPA5
Gene ID 415113
Protein Existence Status Reviewed: Experimental evidence at transcript level

Secondary Information

Protein Function immunoglobulin heavy chain binding protein1 and as the glucose regulated protein; ER-located member of the family of HSP70 molecular chaperones; binds transiently to newly-synthesized proteins in the ER and more permanently to misfolded,underglycosylated or unassembled proteins whose transport from the ER is blocked; assists the folding and assembly of newly-synthesized proteins by recognising unfolded polypeptides and,by inhibiting intra- or intermolecular aggregation,maintaining them in a state competent for subsequent folding and oligomerisation; maintain the permeability barrier of the ER membrane by sealing the lumenal end of the translocon pore before and early in translocation; required during ara cell mating for the stage of karyogamy that involves fusion of the nuclear membranes of Saccharomyces cerevisiae.  BiP is an essential component of the translocation machinery for protein import into the ER, a regulator for Ca2+ homeostasis in the ER, as well as a facilitator of ER-associated protein degradation (ERAD) via retrograde transportation of aberrant proteins across the ER membrane. 
Biochemical Properties BiP does not interact with native polypeptides; two major domains, an N-terminal domain that contains the ATPase catalytic site and a C-terminal substrate bind- ing domain; domains communicate to regulate the affinity and duration of poly.peptide binding; In vitro, BiP can interact with short synthetic peptides whose binding stimulates its ATPase activity and alters its oligomeric state; interacts with sequences normally located in the interior of a fully-folded protein; presence of a heptameric motif with a bulky aromatic or hydrophobic residue most frequently tryptophan, phenylalanine or leucine, but also methionine and isoleucine.
Significance in milk required for mammary gland development; contributes to the regulation of Cripto signaling in mammary stem cells; . Grp78 heterozygosity impeded transgene-induced mammary tumor development, with the tumors showing reduced proliferation, increased apoptosis, and dramatic reduction of tumor angiogenesis
PTMs mammalian BiP exists in interconvertible monomeric and oligomeric forms and can be post-translationally modified by phosphorylation and by ADP ribosylation
Site(s) of PTM(s)

N-glycosylation, O-glycosylation,
Predicted Disorder Regions 1-25,635-655
DisProt Annotation
TM Helix Prediction No TM helices
Significance of PTMs important in regulating the synthesis and polypeptide binding activity of the molecule; conditions that increase the levels of unfolded polypeptides in the ER lumen cause a decrease in the extent of modification of BiP and an increase in the proportion of monomeric species; post-translational modification of BiP appears to provide a storage pool of BiP that can be recruited back to the active form in response to need
Additional Comments  BiP is expressed in arginine vasopressin (AVP) neurons under non-stress conditions and that BiP expression is upregulated in proportion to the increased AVP expression under dehydration.
Bibliography 1. Panayi, G. S. and Corrigall, V. M. (2014) Immunoglobulin heavy-chain-binding protein (BiP): a stress protein that has the potential to be a novel therapy for rheumatoid arthritis. Biochem. Soc. Trans. 42, 1752–1755.
2. Pouysségur, J., Shiu, R. P., and Pastan, I. (1977) Induction of two transformation-sensitive membrane polypeptides in normal fibroblasts by a block in glycoprotein synthesis or glucose deprivation. Cell 11, 941–947.
3. Munro, S. and Pelham, H. R. (1986) An Hsp70-like protein in the ER: identity with the 78 kd glucose-regulated protein and immunoglobulin heavy chain binding protein. Cell 46, 291–300.
4. McKay, D. B. (1993) Structure and mechanism of 70-kDa heat-shock-related proteins. Adv. Protein Chem. 44, 67–98.
5. Flynn, G. C., Chappell, T. G., and Rothman, J. E. (1989) Peptide binding and release by proteins implicated as catalysts of protein assembly. Science 245, 385–390.
6. Blond-Elguindi, S., Cwirla, S. E., Dower, W. J., Lipshutz, R. J., Sprang, S. R., Sambrook, J. F., and Gething, M. J. (1993) Affinity panning of a library of peptides displayed on bacteriophages reveals the binding specificity of BiP. Cell 75, 717–728.
7. Blond-Elguindi, S., Fourie, A. M., Sambrook, J. F., and Gething, M. J. (1993) Peptide-dependent stimulation of the ATPase activity of the molecular chaperone BiP is the result of conversion of oligomers to active monomers. J. Biol. Chem. 268, 12730–12735.
8. Fourie, A. M., Sambrook, J. F., and Gething, M. J. (1994) Common and divergent peptide binding specificities of hsp70 molecular chaperones. J. Biol. Chem. 269, 30470–30478.
9. Knarr, G., Gething, M. J., Modrow, S., and Buchner, J. (1995) BiP binding sequences in antibodies. J. Biol. Chem. 270, 27589–27594.
10. Flaherty, K. M., DeLuca-Flaherty, C., and McKay, D. B. (1990) Three-dimensional structure of the ATPase fragment of a 70K heat-shock cognate protein. Nature 346, 623–628.
11. Zhu, X., Zhao, X., Burkholder, W. F., Gragerov, A., Ogata, C. M., Gottesman, M. E., and Hendrickson, W. A. (1996) Structural analysis of substrate binding by the molecular chaperone DnaK. Science 272, 1606–1614.
12. Nishikawa, S. and Endo, T. (1997) The yeast JEM1p is a DnaJ-like protein of the endoplasmic reticulum membrane required for nuclear fusion. J. Biol. Chem. 272, 12889–12892.
13. Brodsky, J. L. and Schekman, R. (1993) A Sec63p-BiP complex from yeast is required for protein translocation in a reconstituted proteoliposome. J. Cell Biol. 123, 1355–1363.
14. Lyman, S. K. and Schekman, R. (1997) Binding of secretory precursor polypeptides to a translocon subcomplex is regulated by BiP. Cell 88, 85–96.
15. Carlsson, L. and Lazarides, E. (1983) ADP-ribosylation of the Mr 83,000 stress-inducible and glucose-regulated protein in avian and mammalian cells: modulation by heat shock and glucose starvation. Proc. Natl. Acad. Sci. U. S. A. 80, 4664–4668. 16.Wang J, Lee J, Liem D, Ping P. HSPA5 Gene encoding Hsp70 chaperone BiP in the endoplasmic reticulum. Gene. 2017 Jun 30;618:14-23. doi: 10.1016/j.gene.2017.03.005. Epub 2017 Mar 7. PMID: 28286085; PMCID: PMC5632570.