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Biology:Binding immunoglobulin protein

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Binding immunoglobulin protein (BiPS) 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 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.[3]

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).[4][5][6] 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.[7][8][9] An inter-domain linker connects NBD and SBD, favoring the 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 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.[2] The level of BiP 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 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.[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]

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.[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 UPR, and an essential regulator of the UPR pathway.[23][24] During ER stress, BiP dissociates from the three transducers (IRE1, PERK, and ATF6), effectively activating their respective UPR pathways.[25] As a UPR target gene product, BiP is upregulated when UPR transcription factors associate with the UPR element in BiP's DNA promoter region.[26]

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.[14] BiP is also a validated substrate of HYPE (Huntingtin Yeast Interacting Partner E), which can adenylate BiP at multiple residues.[27]

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.[28] 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.[29][30][31] 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.[29][30] 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.[32]

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 Felis silvestris 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.[33] Specifically, it feeds anti-inflammatory and pro-resolutory signals into immune networks, thus helping to resolve inflammation.[34] 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.[35][36]

The potent immunomodulatory activities of BiP/GRP78 have also been demonstrated in animal models of autoimmune disease including collagen-induced arthritis,[37] 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.[38]

Cardiovascular disease

Upregulation of BiP has been associated with ER stress-induced cardiac dysfunction and dilated cardiomyopathy.[39][40] 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.[41]

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.[42]

Neurodegenerative disease

As an ER chaperone protein, BiP prevents neuronal cell death induced by ER stress by correcting misfolded proteins.[43][44] Moreover, a chemical inducer of BiP, named BIX, reduced cerebral infarction in cerebral ischemic mice.[45] Conversely, enhanced BiP chaperone function has been strongly implicated in Alzheimer's disease.[41][46]

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.[47]

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.[46] Meanwhile, a virulent strain of Shiga toxigenic Escherichia coli undermines host cell survival by producing AB5 toxin to inhibit host BiP.[41] 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.[46][48]

Notes


References

  1. ↑ "Human gene encoding the 78,000-dalton glucose-regulated protein and its pseudogene: structure, conservation, and regulation". DNA 7 (4): 275–86. May 1988. doi:10.1089/dna.1988.7.275. PMID 2840249. 
  2. ↑ 2.0 2.1 "Localization of the gene encoding human BiP/GRP78, the endoplasmic reticulum cognate of the HSP70 family, to chromosome 9q34". Genomics 20 (2): 281–4. Mar 1994. doi:10.1006/geno.1994.1166. PMID 8020977. 
  3. ↑ 3.0 3.1 "Close and Allosteric Opening of the Polypeptide-Binding Site in a Human Hsp70 Chaperone BiP". Structure 23 (12): 2191–203. Dec 2015. doi:10.1016/j.str.2015.10.012. PMID 26655470. 
  4. ↑ "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. Oct 1997. doi:10.1002/pro.5560061020. PMID 9336848. 
  5. ↑ 5.0 5.1 "Hsp70 chaperones: cellular functions and molecular mechanism". Cellular and Molecular Life Sciences 62 (6): 670–84. Mar 2005. doi:10.1007/s00018-004-4464-6. PMID 15770419. 
  6. ↑ "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. 2010-01-01. doi:10.1371/journal.pone.0008625. PMID 20072699. Bibcode: 2010PLoSO...5.8625W. 
  7. ↑ "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. Jun 2015. doi:10.1073/pnas.1506692112. PMID 26038563. Bibcode: 2015PNAS..112E2865Z. 
  8. ↑ "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. Nov 2014. doi:10.1021/cb500236y. PMID 25148104. 
  9. ↑ "Allosteric coupling between the lid and interdomain linker in DnaK revealed by inhibitor binding studies". Journal of Bacteriology 191 (5): 1456–62. Mar 2009. doi:10.1128/JB.01131-08. PMID 19103929. 
  10. ↑ "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. Oct 1994. doi:10.1073/pnas.91.22.10345. PMID 7937953. Bibcode: 1994PNAS...9110345S. 
  11. ↑ "Kinetics of molecular chaperone action". Science 263 (5149): 971–3. 1994. doi:10.1126/science.8310296. PMID 8310296. Bibcode: 1994Sci...263..971S. 
  12. ↑ "Allostery in the Hsp70 chaperone proteins". Molecular Chaperones. Topics in Current Chemistry. 328. Springer Berlin Heidelberg. 2012-01-01. pp. 99–153. doi:10.1007/128_2012_323. ISBN 978-3-642-34551-7. 
  13. ↑ "BiP and PDI cooperate in the oxidative folding of antibodies in vitro". The Journal of Biological Chemistry 275 (38): 29421–5. Sep 2000. doi:10.1074/jbc.M002655200. PMID 10893409. 
  14. ↑ 14.0 14.1 "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. April 2015. doi:10.1016/j.jmb.2015.02.011. PMID 25698114. 
  15. ↑ "Development of a novel ER stress based selection system for the isolation of highly productive clones". Biotechnology and Bioengineering 109 (10): 2599–611. Oct 2012. doi:10.1002/bit.24527. PMID 22510960. 
  16. ↑ "BiP/Kar2p serves as a molecular chaperone during carboxypeptidase Y folding in yeast". The Journal of Cell Biology 130 (1): 41–9. Jul 1995. doi:10.1083/jcb.130.1.41. PMID 7790376. 
  17. ↑ "Loss of BiP/GRP78 function blocks translocation of secretory proteins in yeast". The Journal of Cell Biology 110 (6): 1885–95. Jun 1990. doi:10.1083/jcb.110.6.1885. PMID 2190988. 
  18. ↑ "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. Feb 1991. doi:10.1073/pnas.88.4.1565. PMID 1996357. Bibcode: 1991PNAS...88.1565N. 
  19. ↑ "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. Dec 1993. doi:10.1083/jcb.123.6.1355. PMID 8253836. 
  20. ↑ "Endoplasmic reticulum associated protein degradation: a chaperone assisted journey to hell". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1803 (6): 694–705. Jun 2010. doi:10.1016/j.bbamcr.2010.02.005. PMID 20219571. 
  21. ↑ "Mutant analysis links the translocon and BiP to retrograde protein transport for ER degradation". Nature 388 (6645): 891–5. Aug 1997. doi:10.1038/42276. PMID 9278052. Bibcode: 1997Natur.388..891P. 
  22. ↑ "Roles of molecular chaperones in endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD)". Journal of Biochemistry 137 (5): 551–5. May 2005. doi:10.1093/jb/mvi068. PMID 15944407. 
  23. ↑ "Intracellular signaling from the endoplasmic reticulum to the nucleus". Annual Review of Cell and Developmental Biology 14: 459–85. 1998-01-01. doi:10.1146/annurev.cellbio.14.1.459. PMID 9891790. 
  24. ↑ "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. December 2000. doi:10.1006/bbrc.2000.3987. PMID 11118306. 
  25. ↑ "Structural basis of the unfolded protein response". Annual Review of Cell and Developmental Biology 28: 251–77. 2012. doi:10.1146/annurev-cellbio-101011-155826. PMID 23057742. 
  26. ↑ "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. December 2001. doi:10.1016/s0092-8674(01)00611-0. PMID 11779464. 
  27. ↑ "A novel link between Fic (filamentation induced by cAMP)-mediated adenylylation/AMPylation and the unfolded protein response". The Journal of Biological Chemistry 290 (13): 8482–99. March 2015. doi:10.1074/jbc.M114.618348. PMID 25601083. 
  28. ↑ "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. 2008-01-23. doi:10.1186/1471-2148-8-19. PMID 18215318. 
  29. ↑ 29.0 29.1 "Redox signaling via the molecular chaperone BiP protects cells against endoplasmic reticulum-derived oxidative stress". eLife 3: e03496. 2014-07-22. doi:10.7554/eLife.03496. PMID 25053742. 
  30. ↑ 30.0 30.1 "Formation and Reversibility of BiP Cysteine Oxidation Facilitates Cell Survival During and Post Oxidative Stress". The Journal of Biological Chemistry 291 (14): 7541–57. Feb 2016. doi:10.1074/jbc.M115.694810. PMID 26865632. 
  31. ↑ "Loss of the oxidative stress sensor NPGPx compromises GRP78 chaperone activity and induces systemic disease". Molecular Cell 48 (5): 747–59. Dec 2012. doi:10.1016/j.molcel.2012.10.007. PMID 23123197. 
  32. ↑ "Loss of the oxidative stress sensor NPGPx compromises GRP78 chaperone activity and induces systemic disease". Molecular Cell 48 (5): 747–59. December 2012. doi:10.1016/j.molcel.2012.10.007. PMID 23123197. 
  33. ↑ "Stress cytokines: pivotal proteins in immune regulatory networks; Opinion". Current Opinion in Immunology 16 (4): 531–4. August 2004. doi:10.1016/j.coi.2004.05.017. PMID 15245751. 
  34. ↑ "Resolution-associated molecular patterns (RAMP): RAMParts defending immunological homeostasis?". Clinical and Experimental Immunology 165 (3): 292–300. September 2011. doi:10.1111/j.1365-2249.2011.04433.x. PMID 21671907. 
  35. ↑ "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. April 2004. doi:10.1002/art.20134. PMID 15077298. 
  36. ↑ "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. October 2009. doi:10.1111/j.1365-2567.2009.03103.x. PMID 19740378. 
  37. ↑ "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. February 2001. doi:10.4049/jimmunol.166.3.1492. PMID 11160188. 
  38. ↑ "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. March 2006. doi:10.1002/art.21654. PMID 16508967. 
  39. ↑ "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. March 2013. doi:10.1152/ajpheart.00752.2012. PMID 23316062. 
  40. ↑ "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. August 2004. doi:10.1161/01.CIR.0000137836.95625.D4. PMID 15289376. 
  41. ↑ 41.0 41.1 41.2 "ER chaperones in mammalian development and human diseases". FEBS Letters 581 (19): 3641–51. July 2007. doi:10.1016/j.febslet.2007.04.045. PMID 17481612. 
  42. ↑ "Overexpression of endoplasmic reticulum-resident chaperone attenuates cardiomyocyte death induced by proteasome inhibition". Cardiovascular Research 79 (4): 600–10. September 2008. doi:10.1093/cvr/cvn128. PMID 18508854. 
  43. ↑ "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. September 2005. doi:10.1038/ng1620. PMID 16116427. 
  44. ↑ "The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone". Nature Genetics 37 (12): 1309–11. December 2005. doi:10.1038/ng1677. PMID 16282978. 
  45. ↑ "A molecular chaperone inducer protects neurons from ER stress". Cell Death and Differentiation 15 (2): 364–75. February 2008. doi:10.1038/sj.cdd.4402276. PMID 18049481. 
  46. ↑ 46.0 46.1 46.2 "GRP78/BiP/HSPA5/Dna K is a universal therapeutic target for human disease". Journal of Cellular Physiology 230 (7): 1661–76. July 2015. doi:10.1002/jcp.24919. PMID 25546329. 
  47. ↑ "Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis". Nature Medicine 11 (7): 757–64. July 2005. doi:10.1038/nm1259. PMID 15980866. https://lirias.kuleuven.be/handle/123456789/9016. 
  48. ↑ "Differential unfolded protein response during Chikungunya and Sindbis virus infection: CHIKV nsP4 suppresses eIF2α phosphorylation". Virology Journal 10: 36. 28 January 2013. doi:10.1186/1743-422X-10-36. PMID 23356742. 

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