Binding immunoglobulin protein

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Heat shock 70kDa protein 5 (glucose-regulated protein, 78kDa)
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols HSPA5 ; BIP; GRP78; HEL-S-89n; MIF2
External IDs OMIM138120 MGI95835 HomoloGene3908 ChEMBL: 1781865 GeneCards: HSPA5 Gene
RNA expression pattern
PBB GE HSPA5 211936 at tn.png
More reference expression data
Species Human Mouse
Entrez 3309 14828
Ensembl ENSG00000044574 ENSMUSG00000026864
UniProt P11021 P20029
RefSeq (mRNA) NM_005347 NM_001163434
RefSeq (protein) NP_005338 NP_001156906
Location (UCSC) Chr 9:
128 – 128 Mb
Chr 2:
34.77 – 34.78 Mb
PubMed search [1] [2]

Binding immunoglobulin protein (BiP) also known as 78 kDa glucose-regulated protein (GRP-78) or heat shock 70 kDa protein 5 (HSPA5) is a protein that in humans is encoded by the HSPA5 gene.[1][2]

BiP is a HSP70 molecular chaperone located in the lumen of the endoplasmic reticulum (ER) that binds newly synthesized proteins as they are translocated into the ER, and maintains them in a state competent for subsequent folding and oligomerization. BiP is also an essential component of the translocation machinery, as well as playing a role in retrograde transport across the ER membrane of aberrant proteins destined for degradation by the proteasome. BiP is an abundant protein under all growth conditions, but its synthesis is markedly induced under conditions that lead to the accumulation of unfolded polypeptides in the ER.


When Chinese hamster K12 cells are starved of glucose, the synthesis of several proteins, called glucose-regulated proteins (GRPs), is markedly increased. GRP78 (HSPA5), also referred to as 'immunoglobulin heavy chain-binding protein' (BiP), a member of the heat-shock protein-70 (HSP70) family is involved in the folding and assembly of proteins in the endoplasmic reticulum (ER).[2] The level of GRP78 is strongly correlated with the amount of secretory proteins (e.g. IgG) within the ER.[3] Because so many ER proteins interact transiently with GRP78, it is presumed that it may play a key role in assisting protein transport through the cell.[4]


When the nucleotide-binding domain of GRP78 interacts with ATP, its substrate-binding domain can interact with unfolded/misfolded protein. Subsequent ATP hydrolysis acts to strengthen the interaction between GRP78 and the unfolded/misfolded protein. Under these conditions, protein disulfide isomerase (PDI) can then work to promote disulfide reduction, rearrangement, and reoxidation until the correct protein conformation is achieved. ADP/ATP exchange ends the interaction of GRP78 with the protein and thus PDI's work is halted, as well.[5]

Once the correct protein structure is achieved, it is no longer a candidate for GRP78 binding.


Binding immunoglobulin protein has been shown to interact with thyroglobulin[6][7] and SIL1.[8]

Immunological Properties[edit]

Like many stress and heat shock proteins, BiP/GRP78 has potent immunological activity when released from the internal environment of the cell into the extracelluar space.[9] Specifically, it feeds anti-inflammatory and pro-resolutory signals into immune networks, thus helping to resolve inflammation.[10]

The mechanisms underlying BiP's immunological activity are incompletely understood. However, it has been shown that it binds to a receptor on the surface of monocytes and induces anti-inflammatory cytokine secretion dominated by IL-10, IL-1Ra, and soluble TNFR.[11] Furthermore, it downregulates critical molecules involved in T-lymphocyte activation such as HLA-DR and CD86.[11] It also modulates the differentiation pathway of monocytes into dendritic cells, causing them to develop tolerogenic characteristics, which, in turn, can facilitate the development of regulatory T-lymphocytes.[12]

The potent immunomodulatory activities of BiP/GRP78 have also been demonstrated in animal models of autoimmune disease including collagen-induced arthritis,[13] a murine disease that resembles human rheumatoid arthritis. Prophylactic or therapeutic parenteral delivery of BiP has been shown to ameliorate clinical and histological signs of inflammatory arthritis.[14]


Inhibitors of BiP target the ATP-binding domain. Honokiol, a Magnolia grandiflora derivative, is a BiP inhibitor.[15] Inducers of BiP were also found including, BiP inducer X (BIX) was identified in a screen for compounds that induce BiP expression.[16]

See also[edit]


  1. ^ Ting J, Lee AS (May 1988). "Human gene encoding the 78,000-dalton glucose-regulated protein and its pseudogene: structure, conservation, and regulation". DNA 7 (4): 275–86. doi:10.1089/dna.1988.7.275. PMID 2840249. 
  2. ^ a b Hendershot LM, Valentine VA, Lee AS, Morris SW, Shapiro DN (March 1994). "Localization of the gene encoding human BiP/GRP78, the endoplasmic reticulum cognate of the HSP70 family, to chromosome 9q34". Genomics 20 (2): 281–4. doi:10.1006/geno.1994.1166. PMID 8020977. 
  4. ^ "Entrez Gene: HSPA5 heat shock 70kDa protein 5 (glucose-regulated protein, 78kDa)". 
  5. ^ Mayer M, Kies U, Kammermeier R, Buchner J (September 2000). "BiP and PDI cooperate in the oxidative folding of antibodies in vitro". J. Biol. Chem. 275 (38): 29421–5. doi:10.1074/jbc.M002655200. PMID 10893409. 
  6. ^ Delom F, Mallet B, Carayon P, Lejeune PJ (June 2001). "Role of extracellular molecular chaperones in the folding of oxidized proteins. Refolding of colloidal thyroglobulin by protein disulfide isomerase and immunoglobulin heavy chain-binding protein". J. Biol. Chem. 276 (24): 21337–42. doi:10.1074/jbc.M101086200. PMID 11294872. 
  7. ^ Delom F, Lejeune PJ, Vinet L, Carayon P, Mallet B (February 1999). "Involvement of oxidative reactions and extracellular protein chaperones in the rescue of misassembled thyroglobulin in the follicular lumen". Biochem. Biophys. Res. Commun. 255 (2): 438–43. doi:10.1006/bbrc.1999.0229. PMID 10049727. 
  8. ^ Chung KT, Shen Y, Hendershot LM (December 2002). "BAP, a mammalian BiP-associated protein, is a nucleotide exchange factor that regulates the ATPase activity of BiP". J. Biol. Chem. 277 (49): 47557–63. doi:10.1074/jbc.M208377200. PMID 12356756. 
  9. ^ Panayi GS, Corrigall VM, Henderson B (2004). "Stress cytokines: pivotal proteins in immune regulatory networks; Opinion". Current Opinion in Immunology 16 (4): 531–4. doi:10.1016/j.coi.2004.05.017. PMID 15245751. 
  10. ^ Shields AM, Panayi GS, Corrigall VM (2011). "Resolution-associated molecular patterns (RAMP): RAMParts defending immunological homeostasis?". Clin Exp Immunol. 165 (3): 292–300. doi:10.1111/j.1365-2249.2011.04433.x.+Epub+2011+Jun+14. PMC 3170978. PMID 21671907. 
  11. ^ a b Corrigall VM, Bodman-Smith MD, Brunst M, Cornell H, Panayi GS (2004). "Inhibition of antigen-presenting cell function and stimulation of human peripheral blood mononuclear cells to express an antiinflammatory cytokine profile by the stress protein BiP: relevance to the treatment of inflammatory arthritis". Arthritis Rheum. 50 (4): 1164–71. doi:10.1002/art.20134. PMID 15077298. 
  12. ^ Corrigall VM, Vittecoq O, Panayi GS (2009). "Binding immunoglobulin protein-treated peripheral blood monocyte-derived dendritic cells are refractory to maturation and induce regulatory T-cell development". Immunology. 128 (2): 218–26. doi:10.1111/j.1365-2567.2009.03103.x. PMC 2767311. PMID 19740378. 
  13. ^ Corrigall VM, Bodman-Smith MD, Fife MS, Canas B, Myers LK, Wooley P et al. (2001). "The human endoplasmic reticulum molecular chaperone BiP is an autoantigen for rheumatoid arthritis and prevents the induction of experimental arthritis". J Immunol. 166 (3): 1492–8. doi:10.4049/jimmunol.166.3.1492. PMID 11160188. 
  14. ^ Brownlie RJ, Myers LK, Wooley PH, Corrigall VM, Bodman-Smith MD, Panayi GS et al. (2006). "Treatment of murine collagen-induced arthritis by the stress protein BiP via interleukin-4-producing regulatory T cells: a novel function for an ancient protein". Arthritis Rheum. 54 (3): 854–63. doi:10.1002/art.21654. PMID 16508967. 
  15. ^ Martin S, Lamb HK, Brady C, Lefkove B, Bonner MY, Thompson P et al. (July 2013). "Inducing apoptosis of cancer cells using small-molecule plant compounds that bind to GRP78". Br. J. Cancer 109 (2): 433–43. doi:10.1038/bjc.2013.325. PMID 23807168. 
  16. ^ Kudo T, Kanemoto S, Hara H, Morimoto N, Morihara T, Kimura R et al. (February 2008). "A molecular chaperone inducer protects neurons from ER stress". Cell Death Differ. 15 (2): 364–75. doi:10.1038/sj.cdd.4402276. PMID 18049481. 

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