Binding immunoglobulin protein

Heat shock 70kDa protein 5 (glucose-regulated protein, 78kDa)
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols HSPA5 ; BIP; GRP78; HEL-S-89n; MIF2
External IDs OMIM: 138120 MGI: 95835 HomoloGene: 3908 ChEMBL: 1781865 GeneCards: HSPA5 Gene
RNA expression pattern
More reference expression data
Orthologs
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:
125.23 – 125.24 Mb		 Chr 2:
34.77 – 34.78 Mb
PubMed search

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.

Structure

BiP contains two functional domains: a nucleotide-binding domain (NBD) and a substrate-binding domain (SBD). NBD binds and hydrolyzes ATP; the substrates for SBD are extended polypeptides.[3]

NBD consists of two large globular subdomains (I and II), each further divided into two small subdomains (A and B). The subdomains are separated by a cleft where the nucleotide, one Mg2+ and two K+ ions bind and connect all four domains (IA, IB, IIA, IIB).[4][5][6] SBD is divided into two subdomains: SBDβ and SBDα. SBDβ serves as a binding pocket for client proteins or peptide and SBDα serves as a helical lid to cover the binding pocket.[7][8][9] An inter-domain linker connects NBD and SBD, favoring formation of an NBD–SBD interface.[3]

Mechanism

The activity of BiP is regulated by its allosteric ATPase cycle: when ATP is bound to the NBD, the SBDα lid is open, which leads to the conformation of SBD with low affinity to substrate. Upon ATP hydrolysis, ADP is bound to the NBD and the lid closes on the bound substrate. This creates a low off rate for high-affinity substrate binding and protects the bound substrate from premature folding or aggregation. Exchange of ADP for ATP results in the opening of the SBDα lid and subsequent release of the substrate, which then is free to fold.[10][11][12] The ATPase cycle can be synergistically enhanced by protein disulfide isomerase (PDI),[13] and its cochaperones.[14]

Function

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.[15]

Substrate release and binding by BiP facilitates diverse functions in the ER such as folding and assembly of newly synthesized proteins, binding to misfolded proteins to prevent protein aggregation, translocation of secretory proteins, and initiation of the UPR.[5]

Protein foldase and holdase

BiPs can actively fold their substrates (acting as a foldase) or simply bind and restrict a substrate from folding or aggregating (acting as a holdase). Intact ATPase activity and peptide binding activity are required to act as a foldase: temperature-sensitivie mutants of BiP with defective ATPase activity (called class I mutations) and mutants of BiP with defective peptide binding activity (called class II mutations) both fail to fold carboxypeptidase Y (CPY) at non-permissive temperature.[16]

ER translocation

As an ER molecular chaperone, BiP is also required to import polypeptide into the ER lumen or ER membrane in an ATP dependent manner. ATPase mutants of BiP were found to cause a block in translocation of a number of proteins (invertase, carboxypeptidase Y, a-factor) into the lumen of the ER.[17][18][19]

ERAD degradation

BiP is also indicated to play a role in ER associated degradation (ERAD). The most studied ERAD substrate is CPY*, a constitutively misfolded CPY completely imported into the ER and modified by glycosylation. BiP is the first chaperone that contacts CPY* and is required for CPY* degradation.[20] ATPase mutants (including allosteric mutants) of BiP have been shown to significantly slow down the degradation rate of CPY*.[21][22]

UPR pathway

BiP is both a target of the ER stress response, or unfolded protein response (UPR) and an essential regulator of the UPR pathway.[23][24] Two models of UPR pathway initiation by misfolded protein have been proposed:[25] one model poses a competition between unfolded proteins and the sensor domain of IRE1 for binding to BiP. According to this model, unfolded proteins activate IRE1 by binding to BiP and causing its dissociation from the sensor domain.[26][27] An alternative model poses direct binding of unfolded proteins to the sensor domain of IRE1.[28]

Interactions

BiP’s ATPase cycle is facilitated by its co-chaperones, both nucleotide binding factors (NEFs), which facilitate ATP binding upon ADP release, and J proteins, which promote ATP hydrolysis. Specific binding to J proteins and NEFs directs BiP’s ability to achieve a wide array of functions. Two NEFs, Grp170 and Sil1, facilitate substrate release from BiP by stimulating the release of ADP and allowing ATP to rebind and open the lid on the SBD.[14] Seven ERdj co-factors, facilitate ATP hydrolysis of BiP via their J-domains. They assist BiP in various of functions during protein translocation (ERdj2), protein folding (ERdj3 and ERdj6) and ERAD (ERdj4 and ERdj5). The functions of ERdj1 and ERdj7 are not well understood.[14]

Conservation of BiP cysteines

BiP is highly conserved among eukaryotes including mammals (Table 1). it is also widely-expression among all tissue types in human.[29] In the human BiP, there are two highly conserved cysteines. These cysteines have been shown to undergo post-translational modifications in both yeast and mammalian cells.[30][31][32] In yeast cells, the N-terminus cysteine has been shown to be sulfenylated and glutathionylated upon oxidative stress. Both modifications enhance BiP's ability to prevent protein aggregation.[30][31] In mice cells, the conserved cysteine pair forms disulfide bond upon activation of GPx7 (NPGPx). Disulfide bond enhances BiP's binding to denatured proteins.[33]

Table 1. Conservation of BiP in mammalian cells
Species common name Species scientific name Conservation of BiP Conservation of BiP's cysteine Cysteine number
Primates Human Homo sapiens Yes Yes 2
Macaque Macaca fuscata Yes Yes 2
Vervet Chlorocebus sabaeus Predicted* Yes 2
Marmoset Callithrix jacchus Yes Yes 2
Rodents Mouse Mus musculus Yes Yes 2
Rat Rattus norvegicus Yes Yes 3
Guinea pig Cavia porcellus Predicted Yes 3
Naked mole rat Heterocephalus glaber Yes Yes 3
Rabbit Oryctolagus cuniculus Predicted Yes 2
Tree shrew Tupaia chinensis Yes Yes 2
Ungulates Cow Bos taurus Yes Yes 2
Minke whale Balaenoptera acutorostrata scammoni Yes Yes 2
Pig Sus scrofa Predicted Yes 2
Carnivores Dog Canis familiaris Predicted Yes 2
Cat Hammondia hammondi Yes Yes 3
Ferret Mustela putorius furo Predicted Yes 2
Marsupials Opossum Monodelphis domestica Predicted Yes 2
Tasmanian Devil Sarcophilus harrisii Predicted Yes 2
*Predicted: Predicted sequence according to NCBI protein

Clinical significance

Immunological diseases

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.[34] Specifically, it feeds anti-inflammatory and pro-resolutory signals into immune networks, thus helping to resolve inflammation.[35]

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.[36] Furthermore, it downregulates critical molecules involved in T-lymphocyte activation such as HLA-DR and CD86.[36] 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.[37]

The potent immunomodulatory activities of BiP/GRP78 have also been demonstrated in animal models of autoimmune disease including collagen-induced arthritis,[38] 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.[39]

Heart diseases

BiP is recognized by heart infiltrating and peripheral T cells from rheumatic heart disease (RHD) patients. RHD is the major manifestation of RF, is characterized by inflammation of heart valves and myocardium.Identification of BiP as the target antigen suggests BiP may be involved in the autoimmune reactions that leads to valve damage.[40]

As a novel class of anticancer agents, Proteasome inhibitors trigger heart failure through elevation of ER stress.[41] In rat neonatal cardiomyocytes, overexpression of BiP attenuates cardiomyocyte death induced by proteasome inhibition.[42]

BiP inhibitors and enhancers

As a therapeutic target, several BiP inhibitors and enhancers have been developed. Inhibitors of BiP target the ATP-binding domain. Honokiol, a Magnolia grandiflora derivative, is a BiP inhibitor.[43] OSU-03012 (AR-12), The BiP inhibitor OSU-03012 (AR-12), a derivative of the drug celecoxib (Celebrex), interacting with sildenafil (Viagra) or tadalafil (Cialis) can rapidly reduce BiP levels in eukaryotes.[44] Inducers of BiP were also found including, BiP inducer X (BIX) was identified in a screen for compounds that induce BiP expression.[45]

References

  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. 1 2 Hendershot LM, Valentine VA, Lee AS, Morris SW, Shapiro DN (Mar 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.
  3. 1 2 Yang J, Nune M, Zong Y, Zhou L, Liu Q (Dec 2015). "Close and Allosteric Opening of the Polypeptide-Binding Site in a Human Hsp70 Chaperone BiP". Structure 23 (12): 2191–203. doi:10.1016/j.str.2015.10.012. PMC 4680848. PMID 26655470.
  4. ↑ Fairbrother WJ, Champe MA, Christinger HW, Keyt BA, Starovasnik MA (Oct 1997). "1H, 13C, and 15N backbone assignment and secondary structure of the receptor-binding domain of vascular endothelial growth factor". Protein Science 6 (10): 2250–60. doi:10.1002/pro.5560061020. PMC 2143562. PMID 9336848.
  5. 1 2 Mayer MP, Bukau B (Mar 2005). "Hsp70 chaperones: cellular functions and molecular mechanism". Cellular and Molecular Life Sciences 62 (6): 670–84. doi:10.1007/s00018-004-4464-6. PMC 2773841. PMID 15770419.
  6. ↑ Wisniewska M, Karlberg T, Lehtiö L, Johansson I, Kotenyova T, Moche M, Schüler H (2010-01-01). "Crystal structures of the ATPase domains of four human Hsp70 isoforms: HSPA1L/Hsp70-hom, HSPA2/Hsp70-2, HSPA6/Hsp70B', and HSPA5/BiP/GRP78". PloS One 5 (1): e8625. doi:10.1371/journal.pone.0008625. PMC 2803158. PMID 20072699.
  7. ↑ Zhuravleva A, Gierasch LM (Jun 2015). "Substrate-binding domain conformational dynamics mediate Hsp70 allostery". Proceedings of the National Academy of Sciences of the United States of America 112 (22): E2865–73. doi:10.1073/pnas.1506692112. PMC 4460500. PMID 26038563.
  8. ↑ Leu JI, Zhang P, Murphy ME, Marmorstein R, George DL (Nov 2014). "Structural basis for the inhibition of HSP70 and DnaK chaperones by small-molecule targeting of a C-terminal allosteric pocket". ACS Chemical Biology 9 (11): 2508–16. doi:10.1021/cb500236y. PMC 4241170. PMID 25148104.
  9. ↑ Liebscher M, Roujeinikova A (Mar 2009). "Allosteric coupling between the lid and interdomain linker in DnaK revealed by inhibitor binding studies". Journal of Bacteriology 191 (5): 1456–62. doi:10.1128/JB.01131-08. PMC 2648196. PMID 19103929.
  10. ↑ Szabo A, Langer T, Schröder H, Flanagan J, Bukau B, Hartl FU (Oct 1994). "The ATP hydrolysis-dependent reaction cycle of the Escherichia coli Hsp70 system DnaK, DnaJ, and GrpE". Proceedings of the National Academy of Sciences of the United States of America 91 (22): 10345–9. PMC 45016. PMID 7937953.
  11. ↑ Schmid D, Baici A, Gehring H, Christen P (1994). "Kinetics of molecular chaperone action". Science (New York, N.Y.) 263 (5149): 971–3. doi:10.1126/science.8310296. PMID 8310296.
  12. ↑ Zuiderweg ER, Bertelsen EB, Rousaki A, Mayer MP, Gestwicki JE, Ahmad A (2012-01-01). Jackson S, ed. "Allostery in the Hsp70 chaperone proteins". Topics in Current Chemistry. Topics in Current Chemistry (Springer Berlin Heidelberg) 328: 99–153. doi:10.1007/128_2012_323. ISBN 9783642345517. PMC 3623542. PMID 22576356.
  13. ↑ Mayer M, Kies U, Kammermeier R, Buchner J (Sep 2000). "BiP and PDI cooperate in the oxidative folding of antibodies in vitro". The Journal of Biological Chemistry 275 (38): 29421–5. doi:10.1074/jbc.M002655200. PMID 10893409.
  14. 1 2 3 Behnke J, Feige MJ, Hendershot LM (Apr 2015). "BiP and its nucleotide exchange factors Grp170 and Sil1: mechanisms of action and biological functions". Journal of Molecular Biology. Molecular Chaperones and Protein Quality Control (Part I) 427 (7): 1589–608. doi:10.1016/j.jmb.2015.02.011. PMC 4356644. PMID 25698114.
  15. ↑ Kober L, Zehe C, Bode J (Oct 2012). "Development of a novel ER stress based selection system for the isolation of highly productive clones". Biotechnology and Bioengineering 109 (10): 2599–611. doi:10.1002/bit.24527. PMID 22510960.
  16. ↑ Simons JF, Ferro-Novick S, Rose MD, Helenius A (Jul 1995). "BiP/Kar2p serves as a molecular chaperone during carboxypeptidase Y folding in yeast". The Journal of Cell Biology 130 (1): 41–9. PMC 2120506. PMID 7790376.
  17. ↑ Vogel JP, Misra LM, Rose MD (Jun 1990). "Loss of BiP/GRP78 function blocks translocation of secretory proteins in yeast". The Journal of Cell Biology 110 (6): 1885–95. PMC 2116122. PMID 2190988.
  18. ↑ Nguyen TH, Law DT, Williams DB (Feb 1991). "Binding protein BiP is required for translocation of secretory proteins into the endoplasmic reticulum in Saccharomyces cerevisiae". Proceedings of the National Academy of Sciences of the United States of America 88 (4): 1565–9. PMC 51060. PMID 1996357.
  19. ↑ Brodsky JL, Schekman R (Dec 1993). "A Sec63p-BiP complex from yeast is required for protein translocation in a reconstituted proteoliposome". The Journal of Cell Biology 123 (6 Pt 1): 1355–63. PMC 2290880. PMID 8253836.
  20. ↑ Stolz A, Wolf DH (Jun 2010). "Endoplasmic reticulum associated protein degradation: a chaperone assisted journey to hell". Biochimica et Biophysica Acta 1803 (6): 694–705. doi:10.1016/j.bbamcr.2010.02.005. PMID 20219571.
  21. ↑ Plemper RK, Böhmler S, Bordallo J, Sommer T, Wolf DH (Aug 1997). "Mutant analysis links the translocon and BiP to retrograde protein transport for ER degradation". Nature 388 (6645): 891–5. doi:10.1038/42276. PMID 9278052.
  22. ↑ Nishikawa S, Brodsky JL, Nakatsukasa K (May 2005). "Roles of molecular chaperones in endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD)". Journal of Biochemistry 137 (5): 551–5. doi:10.1093/jb/mvi068. PMID 15944407.
  23. ↑ Chapman R, Sidrauski C, Walter P (1998-01-01). "Intracellular signaling from the endoplasmic reticulum to the nucleus". Annual Review of Cell and Developmental Biology 14: 459–85. doi:10.1146/annurev.cellbio.14.1.459. PMID 9891790.
  24. ↑ Okamura K, Kimata Y, Higashio H, Tsuru A, Kohno K (Dec 2000). "Dissociation of Kar2p/BiP from an ER sensory molecule, Ire1p, triggers the unfolded protein response in yeast". Biochemical and Biophysical Research Communications 279 (2): 445–50. doi:10.1006/bbrc.2000.3987. PMID 11118306.
  25. ↑ Korennykh A, Walter P (2012-01-01). "Structural basis of the unfolded protein response". Annual Review of Cell and Developmental Biology 28: 251–77. doi:10.1146/annurev-cellbio-101011-155826. PMID 23057742.
  26. ↑ Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D (Jun 2000). "Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response". Nature Cell Biology 2 (6): 326–32. doi:10.1038/35014014. PMID 10854322.
  27. ↑ Zhou J, Liu CY, Back SH, Clark RL, Peisach D, Xu Z, Kaufman RJ (Sep 2006). "The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response". Proceedings of the National Academy of Sciences of the United States of America 103 (39): 14343–8. doi:10.1073/pnas.0606480103. PMC 1566190. PMID 16973740.
  28. ↑ Credle JJ, Finer-Moore JS, Papa FR, Stroud RM, Walter P (Dec 2005). "On the mechanism of sensing unfolded protein in the endoplasmic reticulum". Proceedings of the National Academy of Sciences of the United States of America 102 (52): 18773–84. doi:10.1073/pnas.0509487102. PMC 1316886. PMID 16365312.
  29. ↑ Brocchieri L, Conway de Macario E, Macario AJ (2008-01-23). "hsp70 genes in the human genome: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions". BMC Evolutionary Biology 8 (1): 19. doi:10.1186/1471-2148-8-19. PMC 2266713. PMID 18215318.
  30. 1 2 Wang J, Pareja KA, Kaiser CA, Sevier CS (2014-07-22). "Redox signaling via the molecular chaperone BiP protects cells against endoplasmic reticulum-derived oxidative stress". eLife 3: e03496. doi:10.7554/eLife.03496. PMC 4132286. PMID 25053742.
  31. 1 2 Wang J, Sevier CS (Feb 2016). "Formation and Reversibility of BiP Cysteine Oxidation Facilitates Cell Survival During and Post Oxidative Stress". The Journal of Biological Chemistry. doi:10.1074/jbc.M115.694810. PMID 26865632.
  32. ↑ Wei PC, Hsieh YH, Su MI, Jiang X, Hsu PH, Lo WT, Weng JY, Jeng YM, Wang JM, Chen PL, Chang YC, Lee KF, Tsai MD, Shew JY, Lee WH (Dec 2012). "Loss of the oxidative stress sensor NPGPx compromises GRP78 chaperone activity and induces systemic disease". Molecular Cell 48 (5): 747–59. doi:10.1016/j.molcel.2012.10.007. PMC 3582359. PMID 23123197.
  33. ↑ Wei PC, Hsieh YH, Su MI, Jiang X, Hsu PH, Lo WT, Weng JY, Jeng YM, Wang JM, Chen PL, Chang YC, Lee KF, Tsai MD, Shew JY, Lee WH (December 2012). "Loss of the oxidative stress sensor NPGPx compromises GRP78 chaperone activity and induces systemic disease". Molecular Cell 48 (5): 747–59. doi:10.1016/j.molcel.2012.10.007. PMC 3582359. PMID 23123197.
  34. ↑ Panayi GS, Corrigall VM, Henderson B (Aug 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.
  35. ↑ Shields AM, Panayi GS, Corrigall VM (Sep 2011). "Resolution-associated molecular patterns (RAMP): RAMParts defending immunological homeostasis?". Clinical and Experimental Immunology 165 (3): 292–300. doi:10.1111/j.1365-2249.2011.04433.x. PMC 3170978. PMID 21671907.
  36. 1 2 Corrigall VM, Bodman-Smith MD, Brunst M, Cornell H, Panayi GS (Apr 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 and Rheumatism 50 (4): 1164–71. doi:10.1002/art.20134. PMID 15077298.
  37. ↑ Corrigall VM, Vittecoq O, Panayi GS (Oct 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.
  38. ↑ Corrigall VM, Bodman-Smith MD, Fife MS, Canas B, Myers LK, Wooley P, Soh C, Staines NA, Pappin DJ, Berlo SE, van Eden W, van Der Zee R, Lanchbury JS, Panayi GS (Feb 2001). "The human endoplasmic reticulum molecular chaperone BiP is an autoantigen for rheumatoid arthritis and prevents the induction of experimental arthritis". Journal of Immunology 166 (3): 1492–8. doi:10.4049/jimmunol.166.3.1492. PMID 11160188.
  39. ↑ Brownlie RJ, Myers LK, Wooley PH, Corrigall VM, Bodman-Smith MD, Panayi GS, Thompson SJ (Mar 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 and Rheumatism 54 (3): 854–63. doi:10.1002/art.21654. PMID 16508967.
  40. ↑ Faé KC, Diefenbach da Silva D, Bilate AM, Tanaka AC, Pomerantzeff PM, Kiss MH, Silva CA, Cunha-Neto E, Kalil J, Guilherme L (Sep 2008). "PDIA3, HSPA5 and vimentin, proteins identified by 2-DE in the valvular tissue, are the target antigens of peripheral and heart infiltrating T cells from chronic rheumatic heart disease patients". Journal of Autoimmunity 31 (2): 136–41. doi:10.1016/j.jaut.2008.04.023. PMID 18541406.
  41. ↑ Okada K, Minamino T, Tsukamoto Y, Liao Y, Tsukamoto O, Takashima S, Hirata A, Fujita M, Nagamachi Y, Nakatani T, Yutani C, Ozawa K, Ogawa S, Tomoike H, Hori M, Kitakaze M (Aug 2004). "Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis". Circulation 110 (6): 705–12. doi:10.1161/01.CIR.0000137836.95625.D4. PMID 15289376.
  42. ↑ Fu HY, Minamino T, Tsukamoto O, Sawada T, Asai M, Kato H, Asano Y, Fujita M, Takashima S, Hori M, Kitakaze M (Sep 2008). "Overexpression of endoplasmic reticulum-resident chaperone attenuates cardiomyocyte death induced by proteasome inhibition". Cardiovascular Research 79 (4): 600–10. doi:10.1093/cvr/cvn128. PMID 18508854.
  43. ↑ Martin S, Lamb HK, Brady C, Lefkove B, Bonner MY, Thompson P, Lovat PE, Arbiser JL, Hawkins AR, Redfern CP (Jul 2013). "Inducing apoptosis of cancer cells using small-molecule plant compounds that bind to GRP78". British Journal of Cancer 109 (2): 433–43. doi:10.1038/bjc.2013.325. PMID 23807168.
  44. ↑ Booth L, Roberts JL, Cash DR, Tavallai S, Jean S, Fidanza A, Cruz-Luna T, Siembiba P, Cycon KA, Cornelissen CN, Dent P (Jul 2015). "GRP78/BiP/HSPA5/Dna K is a universal therapeutic target for human disease". Journal of Cellular Physiology 230 (7): 1661–76. doi:10.1002/jcp.24919. PMC 4402027. PMID 25546329.
  45. ↑ Kudo T, Kanemoto S, Hara H, Morimoto N, Morihara T, Kimura R, Tabira T, Imaizumi K, Takeda M (Feb 2008). "A molecular chaperone inducer protects neurons from ER stress". Cell Death and Differentiation 15 (2): 364–75. doi:10.1038/sj.cdd.4402276. PMID 18049481.

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