Binding immunoglobulin protein

HSPA5
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
Aliases HSPA5, BIP, GRP78, HEL-S-89n, MIF2, Binding immunoglobulin protein, heat shock protein family A (Hsp70) member 5
External IDs MGI: 95835 HomoloGene: 3908 GeneCards: HSPA5
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
NM_022310

RefSeq (protein)

NP_005338.1

NP_001156906.1
NP_071705.3

Location (UCSC) Chr 9: 125.23 – 125.24 Mb Chr 2: 34.77 – 34.78 Mb
PubMed search [1] [2]
Wikidata
View/Edit HumanView/Edit Mouse

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.[3][4]

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 and plays 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). The NBD binds and hydrolyzes ATP, and the SBD binds polypeptides.[5]

The 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).[6][7][8] The 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.[9][10][11] An inter-domain linker connects NBD and SBD, favoring the irformation of an NBD–SBD interface.[5]

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.[12][13][14] The ATPase cycle can be synergistically enhanced by protein disulfide isomerase (PDI),[15] and its cochaperones.[16]

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), is a member of the heat-shock protein-70 (HSP70) family and involved in the folding and assembly of proteins in the ER.[4] The level of BiP is strongly correlated with the amount of secretory proteins (e.g. IgG) within the ER.[17]

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.[7]

Protein folding and holding

BiP can actively fold its 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-sensitive 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.[18]

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.[19][20][21]

ER-associated degradation (ERAD)

BiP also plays a role in 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.[22] ATPase mutants (including allosteric mutants) of BiP have been shown to significantly slow down the degradation rate of CPY*.[23][24]

UPR pathway

BiP is both a target of the ER stress response, or UPR, and an essential regulator of the UPR pathway.[25][26] During ER stress, BiP dissociates from the three transducers (IRE1, PERK, and ATF6), effectively activating their respective UPR pathways.[27] As a UPR target gene product, BiP is upregulated when UPR transcription factors associate with the UPR element in BiP’s DNA promoter region.[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.[16]

Conservation of BiP cysteines

BiP is highly conserved among eukaryotes, including mammals (Table 1). It is also widely expressed 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 a disulfide bond upon activation of GPx7 (NPGPx). The 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

Autoimmune disease

Like many stress and heat shock proteins, BiP has potent immunological activity when released from the internal environment of the cell into the extracellular 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. Nonetheless, it has been shown to induce anti-inflammatory cytokine secretion by binding to a receptor on the surface of monocytes, downregulate critical molecules involved in T-lymphocyte activation, and modulate the differentiation pathway of monocytes into dendritic cells.[36][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]

Cardiovascular disease

Upregulation of BiP has been associated with ER stress-induced cardiac dysfunction and dilated cardiomyopathy.[40][41] BiP also has been proposed to suppress the development of atherosclerosis through alleviating homocysteine-induced ER stress, preventing apoptosis of vascular endothelial cells, inhibiting the activation of genes responsible for cholesterol/triglyceride biosynthesis, and suppressing tissue factor procoagulant activity, all of which can contribute to the buildup of atherosclerotic plaques.[42]

Some anticancer drugs, such as proteasome inhibitors, have been associated with heart failure complications. In rat neonatal cardiomyocytes, overexpression of BiP attenuates cardiomyocyte death induced by proteasome inhibition.[43]

Neurodegenerative disease

As an ER chaperone protein, BiP prevents neuronal cell death induced by ER stress by correcting misfolded proteins.[44][45] Moreover, a chemical inducer of BiP, named BIX, reduced cerebral infarction in cerebral ischemic mice.[46][45] Conversely, enhanced BiP chaperone function has been strongly implicated in Alzheimer’s disease.[42][47]

Metabolic disease

BiP heterozygosity is proposed to protect against high fat diet-induced obesity, type 2 diabetes, and pancreatitis by upregulating protective ER stress pathways. BiP is also necessary for adipogenesis and glucose homeostasis in adipose tissues.[48]

Infectious disease

Prokaryotic BiP orthologs were found to interact with key proteins such as RecA, which is vital to bacterial DNA replication. As a result, these bacterial Hsp70 chaperones represent a promising set of targets for antibiotic development. Notably, the anticancer drug OSU-03012 re-sensitized superbug strains of Neisseria gonorrhoeae to several standard-of-care antibiotics.[47] Meanwhile, a virulent strain of Shiga toxigenic Escherichia coli undermines host cell survival by producing AB5 toxin to inhibit host BiP.[42] In contrast, viruses rely on host BiP to successfully replicate, largely by infecting cells through cell-surface BiP, stimulating BiP expression to chaperone viral proteins, and suppressing the ER stress death response.[47][49]

References

  1. ↑ "Human PubMed Reference:".
  2. ↑ "Mouse PubMed Reference:".
  3. ↑ 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.
  4. 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.
  5. 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 4680848Freely accessible. PMID 26655470.
  6. ↑ 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 2143562Freely accessible. PMID 9336848.
  7. 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 2773841Freely accessible. PMID 15770419.
  8. ↑ 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 2803158Freely accessible. PMID 20072699.
  9. ↑ 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 4460500Freely accessible. PMID 26038563.
  10. ↑ 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 4241170Freely accessible. PMID 25148104.
  11. ↑ 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 2648196Freely accessible. PMID 19103929.
  12. ↑ 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. doi:10.1073/pnas.91.22.10345. PMC 45016Freely accessible. PMID 7937953.
  13. ↑ Schmid D, Baici A, Gehring H, Christen P (1994). "Kinetics of molecular chaperone action". Science. 263 (5149): 971–3. doi:10.1126/science.8310296. PMID 8310296.
  14. ↑ 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 3623542Freely accessible. PMID 22576356.
  15. ↑ 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.
  16. 1 2 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 4356644Freely accessible. PMID 25698114.
  17. ↑ 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.
  18. ↑ 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. doi:10.1083/jcb.130.1.41. PMC 2120506Freely accessible. PMID 7790376.
  19. ↑ 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. doi:10.1083/jcb.110.6.1885. PMC 2116122Freely accessible. PMID 2190988.
  20. ↑ 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. doi:10.1073/pnas.88.4.1565. PMC 51060Freely accessible. PMID 1996357.
  21. ↑ 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 2290880Freely accessible. PMID 8253836.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ Okamura K, Kimata Y, Higashio H, Tsuru A, Kohno K (December 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.
  27. ↑ Korennykh A, Walter P (2012). "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.
  28. ↑ Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (December 2001). "XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor". Cell. 107 (7): 881–91. doi:10.1016/s0092-8674(01)00611-0. PMID 11779464.
  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 2266713Freely accessible. 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 4132286Freely accessible. 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. 291: 7541–57. 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 3582359Freely accessible. 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 3582359Freely accessible. PMID 23123197.
  34. ↑ Panayi GS, Corrigall VM, Henderson B (August 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 (September 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 3170978Freely accessible. PMID 21671907.
  36. ↑ Corrigall VM, Bodman-Smith MD, Brunst M, Cornell H, Panayi GS (April 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 (October 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 2767311Freely accessible. 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 (February 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 (March 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. ↑ Roe ND, Ren J (March 2013). "Oxidative activation of Ca(2+)/calmodulin-activated kinase II mediates ER stress-induced cardiac dysfunction and apoptosis". American Journal of Physiology. Heart and Circulatory Physiology. 304 (6): H828–39. doi:10.1152/ajpheart.00752.2012. PMC 3602775Freely accessible. PMID 23316062.
  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 (August 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. 1 2 3 Ni M, Lee AS (July 2007). "ER chaperones in mammalian development and human diseases". FEBS Letters. 581 (19): 3641–51. doi:10.1016/j.febslet.2007.04.045. PMC 2040386Freely accessible. PMID 17481612.
  43. ↑ Fu HY, Minamino T, Tsukamoto O, Sawada T, Asai M, Kato H, Asano Y, Fujita M, Takashima S, Hori M, Kitakaze M (September 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.
  44. ↑ Zhao L, Longo-Guess C, Harris BS, Lee JW, Ackerman SL (September 2005). "Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP". Nature Genetics. 37 (9): 974–9. doi:10.1038/ng1620. PMID 16116427.
  45. ↑ Anttonen AK, Mahjneh I, Hämäläinen RH, Lagier-Tourenne C, Kopra O, Waris L, Anttonen M, Joensuu T, Kalimo H, Paetau A, Tranebjaerg L, Chaigne D, Koenig M, Eeg-Olofsson O, Udd B, Somer M, Somer H, Lehesjoki AE (December 2005). "The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone". Nature Genetics. 37 (12): 1309–11. doi:10.1038/ng1677. PMID 16282978.
  46. ↑ Kudo T, Kanemoto S, Hara H, Morimoto N, Morihara T, Kimura R, Tabira T, Imaizumi K, Takeda M (February 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.
  47. 1 2 3 Booth L, Roberts JL, Cash DR, Tavallai S, Jean S, Fidanza A, Cruz-Luna T, Siembiba P, Cycon KA, Cornelissen CN, Dent P (July 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 4402027Freely accessible. PMID 25546329.
  48. ↑ Scheuner D, Vander Mierde D, Song B, Flamez D, Creemers JW, Tsukamoto K, Ribick M, Schuit FC, Kaufman RJ (July 2005). "Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis". Nature Medicine. 11 (7): 757–64. doi:10.1038/nm1259. PMID 15980866.
  49. ↑ Rathore AP, Ng ML, Vasudevan SG (28 January 2013). "Differential unfolded protein response during Chikungunya and Sindbis virus infection: CHIKV nsP4 suppresses eIF2α phosphorylation". Virology Journal. 10: 36. doi:10.1186/1743-422X-10-36. PMC 3605262Freely accessible. PMID 23356742.

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