Binding immunoglobulin protein: Difference between revisions

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'''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]].<ref name="pmid2840249">{{cite journal | vauthors = Ting J, Lee AS | title = Human gene encoding the 78,000-dalton glucose-regulated protein and its pseudogene: structure, conservation, and regulation | journal = DNA | volume = 7 | issue = 4 | pages = 275–86 | date = May 1988 | pmid = 2840249 | doi = 10.1089/dna.1988.7.275 }}</ref><ref name="pmid80209772">{{cite journal | vauthors = Hendershot LM, Valentine VA, Lee AS, Morris SW, Shapiro DN | title = Localization of the gene encoding human BiP/GRP78, the endoplasmic reticulum cognate of the HSP70 family, to chromosome 9q34 | journal = Genomics | volume = 20 | issue = 2 | pages = 281–4 | date = Mar 1994 | pmid = 8020977 | doi = 10.1006/geno.1994.1166 }}</ref>
'''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]].<ref name="pmid2840249">{{cite journal | vauthors = Ting J, Lee AS | title = Human gene encoding the 78,000-dalton glucose-regulated protein and its pseudogene: structure, conservation, and regulation | journal = DNA | volume = 7 | issue = 4 | pages = 275–86 | date = May 1988 | pmid = 2840249 | doi = 10.1089/dna.1988.7.275 }}</ref><ref name="pmid80209772">{{cite journal | vauthors = Hendershot LM, Valentine VA, Lee AS, Morris SW, Shapiro DN | title = Localization of the gene encoding human BiP/GRP78, the endoplasmic reticulum cognate of the HSP70 family, to chromosome 9q34 | journal = Genomics | volume = 20 | issue = 2 | pages = 281–4 | date = Mar 1994 | pmid = 8020977 | doi = 10.1006/geno.1994.1166 }}</ref>


BiP is a [[Hsp70|HSP70]] molecular [[chaperone (protein)|chaperone]] located in the lumen of the [[endoplasmic reticulum]] (ER) that binds newly synthesized proteins as they are [[protein targeting|translocated]] into the ER, and maintains them in a state competent for subsequent [[protein folding|folding]] and [[oligomer]]ization. BiP is also an essential component of the [[Protein targeting|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.
BiP is a [[Hsp70|HSP70]] molecular [[chaperone (protein)|chaperone]] located in the lumen of the [[endoplasmic reticulum]] (ER) that binds newly synthesized proteins as they are [[protein targeting|translocated]] into the ER, and maintains them in a state competent for subsequent [[protein folding|folding]] and [[oligomer]]ization. BiP is also an essential component of the [[Protein targeting|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 ==
== Structure ==


BiP contains two functional [[Protein domain|domain]]s: a nucleotide-binding domain (NBD) and a substrate-binding domain (SBD). NBD binds and hydrolyzes ATP; the substrates for SBD are extended [[polypeptides]].<ref name="Yang_2015">{{cite journal | vauthors = Yang J, Nune M, Zong Y, Zhou L, Liu Q | title = Close and Allosteric Opening of the Polypeptide-Binding Site in a Human Hsp70 Chaperone BiP | journal = Structure | volume = 23 | issue = 12 | pages = 2191–203 | date = Dec 2015 | pmid = 26655470 | pmc = 4680848 | doi = 10.1016/j.str.2015.10.012 }}</ref>
BiP contains two functional [[Protein domain|domain]]s: a nucleotide-binding domain (NBD) and a substrate-binding domain (SBD). The NBD binds and hydrolyzes ATP, and the SBD binds [[polypeptides]].<ref name="Yang_2015">{{cite journal | vauthors = Yang J, Nune M, Zong Y, Zhou L, Liu Q | title = Close and Allosteric Opening of the Polypeptide-Binding Site in a Human Hsp70 Chaperone BiP | journal = Structure | volume = 23 | issue = 12 | pages = 2191–203 | date = Dec 2015 | pmid = 26655470 | pmc = 4680848 | doi = 10.1016/j.str.2015.10.012 }}</ref>


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 Mg<sup>2+</sup> and two K<sup>+</sup> ions bind and connect all four domains (IA, IB, IIA, IIB).<ref>{{cite journal | vauthors = Fairbrother WJ, Champe MA, Christinger HW, Keyt BA, Starovasnik MA | title = 1H, 13C, and 15N backbone assignment and secondary structure of the receptor-binding domain of vascular endothelial growth factor | journal = Protein Science | volume = 6 | issue = 10 | pages = 2250–60 | date = Oct 1997 | pmid = 9336848 | pmc = 2143562 | doi = 10.1002/pro.5560061020 }}</ref><ref name="Mayer_2005">{{cite journal | vauthors = Mayer MP, Bukau B | title = Hsp70 chaperones: cellular functions and molecular mechanism | journal = Cellular and Molecular Life Sciences | volume = 62 | issue = 6 | pages = 670–84 | date = Mar 2005 | pmid = 15770419 | pmc = 2773841 | doi = 10.1007/s00018-004-4464-6 }}</ref><ref>{{cite journal | vauthors = Wisniewska M, Karlberg T, Lehtiö L, Johansson I, Kotenyova T, Moche M, Schüler H | title = Crystal structures of the ATPase domains of four human Hsp70 isoforms: HSPA1L/Hsp70-hom, HSPA2/Hsp70-2, HSPA6/Hsp70B', and HSPA5/BiP/GRP78 | journal = PloS One | volume = 5 | issue = 1 | pages = e8625 | date = 2010-01-01 | pmid = 20072699 | pmc = 2803158 | doi = 10.1371/journal.pone.0008625 }}</ref> 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.<ref>{{cite journal | vauthors = Zhuravleva A, Gierasch LM | title = Substrate-binding domain conformational dynamics mediate Hsp70 allostery | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 22 | pages = E2865-73 | date = Jun 2015 | pmid = 26038563 | pmc = 4460500 | doi = 10.1073/pnas.1506692112 }}</ref><ref>{{cite journal | vauthors = Leu JI, Zhang P, Murphy ME, Marmorstein R, George DL | title = Structural basis for the inhibition of HSP70 and DnaK chaperones by small-molecule targeting of a C-terminal allosteric pocket | journal = ACS Chemical Biology | volume = 9 | issue = 11 | pages = 2508–16 | date = Nov 2014 | pmid = 25148104 | pmc = 4241170 | doi = 10.1021/cb500236y }}</ref><ref>{{cite journal | vauthors = Liebscher M, Roujeinikova A | title = Allosteric coupling between the lid and interdomain linker in DnaK revealed by inhibitor binding studies | journal = Journal of Bacteriology | volume = 191 | issue = 5 | pages = 1456–62 | date = Mar 2009 | pmid = 19103929 | pmc = 2648196 | doi = 10.1128/JB.01131-08 }}</ref> An inter-domain linker connects NBD and SBD, favoring formation of an NBD–SBD interface.<ref name="Yang_2015" />
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 Mg<sup>2+</sup>, and two K<sup>+</sup> ions bind and connect all four domains (IA, IB, IIA, IIB).<ref>{{cite journal | vauthors = Fairbrother WJ, Champe MA, Christinger HW, Keyt BA, Starovasnik MA | title = 1H, 13C, and 15N backbone assignment and secondary structure of the receptor-binding domain of vascular endothelial growth factor | journal = Protein Science | volume = 6 | issue = 10 | pages = 2250–60 | date = Oct 1997 | pmid = 9336848 | pmc = 2143562 | doi = 10.1002/pro.5560061020 }}</ref><ref name="Mayer_2005">{{cite journal | vauthors = Mayer MP, Bukau B | title = Hsp70 chaperones: cellular functions and molecular mechanism | journal = Cellular and Molecular Life Sciences | volume = 62 | issue = 6 | pages = 670–84 | date = Mar 2005 | pmid = 15770419 | pmc = 2773841 | doi = 10.1007/s00018-004-4464-6 }}</ref><ref>{{cite journal | vauthors = Wisniewska M, Karlberg T, Lehtiö L, Johansson I, Kotenyova T, Moche M, Schüler H | title = Crystal structures of the ATPase domains of four human Hsp70 isoforms: HSPA1L/Hsp70-hom, HSPA2/Hsp70-2, HSPA6/Hsp70B', and HSPA5/BiP/GRP78 | journal = PloS One | volume = 5 | issue = 1 | pages = e8625 | date = 2010-01-01 | pmid = 20072699 | pmc = 2803158 | doi = 10.1371/journal.pone.0008625 }}</ref> 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.<ref>{{cite journal | vauthors = Zhuravleva A, Gierasch LM | title = Substrate-binding domain conformational dynamics mediate Hsp70 allostery | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 22 | pages = E2865-73 | date = Jun 2015 | pmid = 26038563 | pmc = 4460500 | doi = 10.1073/pnas.1506692112 }}</ref><ref>{{cite journal | vauthors = Leu JI, Zhang P, Murphy ME, Marmorstein R, George DL | title = Structural basis for the inhibition of HSP70 and DnaK chaperones by small-molecule targeting of a C-terminal allosteric pocket | journal = ACS Chemical Biology | volume = 9 | issue = 11 | pages = 2508–16 | date = Nov 2014 | pmid = 25148104 | pmc = 4241170 | doi = 10.1021/cb500236y }}</ref><ref>{{cite journal | vauthors = Liebscher M, Roujeinikova A | title = Allosteric coupling between the lid and interdomain linker in DnaK revealed by inhibitor binding studies | journal = Journal of Bacteriology | volume = 191 | issue = 5 | pages = 1456–62 | date = Mar 2009 | pmid = 19103929 | pmc = 2648196 | doi = 10.1128/JB.01131-08 }}</ref> An inter-domain linker connects NBD and SBD, favoring the irformation of an NBD–SBD interface.<ref name="Yang_2015" />


== Mechanism ==
== Mechanism ==
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== Function ==
== Function ==


When Chinese hamster K12 cells are starved of glucose, the synthesis of several proteins, called [[glucose-regulated protein]]s (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).<ref name="pmid80209772"/> The level of GRP78 is strongly correlated with the amount of secretory proteins (e.g. IgG) within the ER.<ref name="pmid225109602">{{cite journal | vauthors = Kober L, Zehe C, Bode J | title = Development of a novel ER stress based selection system for the isolation of highly productive clones | journal = Biotechnology and Bioengineering | volume = 109 | issue = 10 | pages = 2599–611 | date = Oct 2012 | pmid = 22510960 | doi = 10.1002/bit.24527 }}</ref>
When Chinese hamster K12 cells are starved of glucose, the synthesis of several proteins, called [[glucose-regulated protein]]s (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.<ref name="pmid80209772"/> The level of BiP is strongly correlated with the amount of secretory proteins (e.g. IgG) within the ER.<ref name="pmid225109602">{{cite journal | vauthors = Kober L, Zehe C, Bode J | title = Development of a novel ER stress based selection system for the isolation of highly productive clones | journal = Biotechnology and Bioengineering | volume = 109 | issue = 10 | pages = 2599–611 | date = Oct 2012 | pmid = 22510960 | doi = 10.1002/bit.24527 }}</ref>


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 [[Protein aggregation|aggregation]], [[protein targeting|translocation]] of [[secretory protein]]s, and initiation of the [[Unfolded protein response|UPR]].<ref name="Mayer_2005" />
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 [[Protein aggregation|aggregation]], [[protein targeting|translocation]] of [[secretory protein]]s, and initiation of the [[Unfolded protein response|UPR]].<ref name="Mayer_2005" />


=== Protein foldase and holdase ===
=== Protein folding and holding ===


BiPs can actively fold their substrates (acting as a [[foldase]]) or simply bind and restrict a substrate from folding or [[Protein aggregation|aggregating]] (acting as a [[holdase]]). Intact ATPase activity and peptide binding activity are required to act as a foldase: [[Permissive temperature|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 [[Permissive temperature|non-permissive temperature]].<ref>{{cite journal | vauthors = Simons JF, Ferro-Novick S, Rose MD, Helenius A | title = BiP/Kar2p serves as a molecular chaperone during carboxypeptidase Y folding in yeast | journal = The Journal of Cell Biology | volume = 130 | issue = 1 | pages = 41–9 | date = Jul 1995 | pmid = 7790376 | pmc = 2120506 }}</ref>
BiP can actively fold its substrates (acting as a [[foldase]]) or simply bind and restrict a substrate from folding or [[Protein aggregation|aggregating]] (acting as a [[holdase]]). Intact ATPase activity and peptide binding activity are required to act as a foldase: [[Permissive temperature|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 [[Permissive temperature|non-permissive temperature]].<ref>{{cite journal | vauthors = Simons JF, Ferro-Novick S, Rose MD, Helenius A | title = BiP/Kar2p serves as a molecular chaperone during carboxypeptidase Y folding in yeast | journal = The Journal of Cell Biology | volume = 130 | issue = 1 | pages = 41–9 | date = Jul 1995 | pmid = 7790376 | pmc = 2120506 }}</ref>


=== ER translocation ===
=== 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, [[Alpha factor|a-factor]]) into the [[lumen (anatomy)|lumen]] of the ER.<ref>{{cite journal | vauthors = Vogel JP, Misra LM, Rose MD | title = Loss of BiP/GRP78 function blocks translocation of secretory proteins in yeast | journal = The Journal of Cell Biology | volume = 110 | issue = 6 | pages = 1885–95 | date = Jun 1990 | pmid = 2190988 | pmc = 2116122 }}</ref><ref>{{cite journal | vauthors = Nguyen TH, Law DT, Williams DB | title = Binding protein BiP is required for translocation of secretory proteins into the endoplasmic reticulum in Saccharomyces cerevisiae | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 4 | pages = 1565–9 | date = Feb 1991 | pmid = 1996357 | pmc = 51060 }}</ref><ref>{{cite journal | vauthors = Brodsky JL, Schekman R | title = A Sec63p-BiP complex from yeast is required for protein translocation in a reconstituted proteoliposome | journal = The Journal of Cell Biology | volume = 123 | issue = 6 Pt 1 | pages = 1355–63 | date = Dec 1993 | pmid = 8253836 | pmc = 2290880 }}</ref>
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, [[Alpha factor|a-factor]]) into the [[lumen (anatomy)|lumen]] of the ER.<ref>{{cite journal | vauthors = Vogel JP, Misra LM, Rose MD | title = Loss of BiP/GRP78 function blocks translocation of secretory proteins in yeast | journal = The Journal of Cell Biology | volume = 110 | issue = 6 | pages = 1885–95 | date = Jun 1990 | pmid = 2190988 | pmc = 2116122 }}</ref><ref>{{cite journal | vauthors = Nguyen TH, Law DT, Williams DB | title = Binding protein BiP is required for translocation of secretory proteins into the endoplasmic reticulum in Saccharomyces cerevisiae | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 4 | pages = 1565–9 | date = Feb 1991 | pmid = 1996357 | pmc = 51060 }}</ref><ref>{{cite journal | vauthors = Brodsky JL, Schekman R | title = A Sec63p-BiP complex from yeast is required for protein translocation in a reconstituted proteoliposome | journal = The Journal of Cell Biology | volume = 123 | issue = 6 Pt 1 | pages = 1355–63 | date = Dec 1993 | pmid = 8253836 | pmc = 2290880 }}</ref>


=== ERAD degradation ===
=== ER-associated degradation (ERAD) ===


BiP is also indicated to play a role in [[ERAD|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.<ref>{{cite journal | vauthors = Stolz A, Wolf DH | title = Endoplasmic reticulum associated protein degradation: a chaperone assisted journey to hell | journal = Biochimica et Biophysica Acta | volume = 1803 | issue = 6 | pages = 694–705 | date = Jun 2010 | pmid = 20219571 | doi = 10.1016/j.bbamcr.2010.02.005 }}</ref> ATPase mutants (including allosteric mutants) of BiP have been shown to significantly slow down the degradation rate of CPY*.<ref>{{cite journal | vauthors = Plemper RK, Böhmler S, Bordallo J, Sommer T, Wolf DH | title = Mutant analysis links the translocon and BiP to retrograde protein transport for ER degradation | journal = Nature | volume = 388 | issue = 6645 | pages = 891–5 | date = Aug 1997 | pmid = 9278052 | doi = 10.1038/42276 }}</ref><ref>{{cite journal | vauthors = Nishikawa S, Brodsky JL, Nakatsukasa K | title = Roles of molecular chaperones in endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD) | journal = Journal of Biochemistry | volume = 137 | issue = 5 | pages = 551–5 | date = May 2005 | pmid = 15944407 | doi = 10.1093/jb/mvi068 }}</ref>
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.<ref>{{cite journal | vauthors = Stolz A, Wolf DH | title = Endoplasmic reticulum associated protein degradation: a chaperone assisted journey to hell | journal = Biochimica et Biophysica Acta | volume = 1803 | issue = 6 | pages = 694–705 | date = Jun 2010 | pmid = 20219571 | doi = 10.1016/j.bbamcr.2010.02.005 }}</ref> ATPase mutants (including allosteric mutants) of BiP have been shown to significantly slow down the degradation rate of CPY*.<ref>{{cite journal | vauthors = Plemper RK, Böhmler S, Bordallo J, Sommer T, Wolf DH | title = Mutant analysis links the translocon and BiP to retrograde protein transport for ER degradation | journal = Nature | volume = 388 | issue = 6645 | pages = 891–5 | date = Aug 1997 | pmid = 9278052 | doi = 10.1038/42276 }}</ref><ref>{{cite journal | vauthors = Nishikawa S, Brodsky JL, Nakatsukasa K | title = Roles of molecular chaperones in endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD) | journal = Journal of Biochemistry | volume = 137 | issue = 5 | pages = 551–5 | date = May 2005 | pmid = 15944407 | doi = 10.1093/jb/mvi068 }}</ref>


=== UPR pathway ===
=== UPR pathway ===


BiP is both a target of the ER stress response, or [[Unfolded protein response|unfolded protein response (UPR)]] and an essential regulator of the UPR pathway.<ref>{{cite journal | vauthors = Chapman R, Sidrauski C, Walter P | title = Intracellular signaling from the endoplasmic reticulum to the nucleus | journal = Annual Review of Cell and Developmental Biology | volume = 14 | pages = 459–85 | date = 1998-01-01 | pmid = 9891790 | doi = 10.1146/annurev.cellbio.14.1.459 }}</ref><ref>{{cite journal | vauthors = Okamura K, Kimata Y, Higashio H, Tsuru A, Kohno K | title = Dissociation of Kar2p/BiP from an ER sensory molecule, Ire1p, triggers the unfolded protein response in yeast | journal = Biochemical and Biophysical Research Communications | volume = 279 | issue = 2 | pages = 445–50 | date = Dec 2000 | pmid = 11118306 | doi = 10.1006/bbrc.2000.3987 }}</ref> Two models of UPR pathway initiation by misfolded protein have been proposed:<ref>{{cite journal | vauthors = Korennykh A, Walter P | title = Structural basis of the unfolded protein response | journal = Annual Review of Cell and Developmental Biology | volume = 28 | pages = 251–77 | date = 2012-01-01 | pmid = 23057742 | doi = 10.1146/annurev-cellbio-101011-155826 }}</ref> one model poses a competition between unfolded proteins and the sensor domain of [[ERN1|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.<ref>{{cite journal | vauthors = Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D | title = Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response | journal = Nature Cell Biology | volume = 2 | issue = 6 | pages = 326–32 | date = Jun 2000 | pmid = 10854322 | doi = 10.1038/35014014 }}</ref><ref>{{cite journal | vauthors = Zhou J, Liu CY, Back SH, Clark RL, Peisach D, Xu Z, Kaufman RJ | title = The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 39 | pages = 14343–8 | date = Sep 2006 | pmid = 16973740 | pmc = 1566190 | doi = 10.1073/pnas.0606480103 }}</ref> An alternative model poses direct binding of unfolded proteins to the sensor domain of IRE1.<ref>{{cite journal | vauthors = Credle JJ, Finer-Moore JS, Papa FR, Stroud RM, Walter P | title = On the mechanism of sensing unfolded protein in the endoplasmic reticulum | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 52 | pages = 18773–84 | date = Dec 2005 | pmid = 16365312 | pmc = 1316886 | doi = 10.1073/pnas.0509487102 }}</ref>
BiP is both a target of the ER stress response, or [[Unfolded protein response|UPR]], and an essential regulator of the UPR pathway.<ref>{{cite journal | vauthors = Chapman R, Sidrauski C, Walter P | title = Intracellular signaling from the endoplasmic reticulum to the nucleus | journal = Annual Review of Cell and Developmental Biology | volume = 14 | pages = 459–85 | date = 1998-01-01 | pmid = 9891790 | doi = 10.1146/annurev.cellbio.14.1.459 }}</ref><ref>{{cite journal | vauthors = Okamura K, Kimata Y, Higashio H, Tsuru A, Kohno K | title = Dissociation of Kar2p/BiP from an ER sensory molecule, Ire1p, triggers the unfolded protein response in yeast | journal = Biochemical and Biophysical Research Communications | volume = 279 | issue = 2 | pages = 445–50 | date = Dec 2000 | pmid = 11118306 | doi = 10.1006/bbrc.2000.3987 }}</ref> During ER stress, BiP dissociates from the three transducers ([[ERN1|IRE1]], [[EIF2AK3|PERK]], and [[ATF6]]), effectively activating their respective UPR pathways.<ref>{{cite journal|last1=Korennykh|first1=A|last2=Walter|first2=P|title=Structural basis of the unfolded protein response.|journal=Annual review of cell and developmental biology|date=2012|volume=28|pages=251-77|pmid=23057742}}</ref> As a UPR target gene product, BiP is upregulated when UPR transcription factors associate with the UPR element in BiP’s DNA promoter region.<ref>{{cite journal|last1=Yoshida|first1=H|last2=Matsui|first2=T|last3=Yamamoto|first3=A|last4=Okada|first4=T|last5=Mori|first5=K|title=XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor.|journal=Cell|date=28 December 2001|volume=107|issue=7|pages=881-91|pmid=11779464}}</ref>


== Interactions ==
== Interactions ==


BiP’s ATPase cycle is facilitated by its [[co-chaperone]]s, both [[Nucleotide exchange factor|nucleotide binding factors (NEFs)]], which facilitate ATP binding upon ADP release, and [[Hsp40|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|Grp170]] and [[SIL1|Sil1]], facilitate substrate release from BiP by stimulating the release of ADP and allowing ATP to rebind and open the lid on the SBD.<ref name="Behnke_2015">{{cite journal | vauthors = Behnke J, Feige MJ, Hendershot LM | title = BiP and its nucleotide exchange factors Grp170 and Sil1: mechanisms of action and biological functions | journal = Journal of Molecular Biology | volume = 427 | issue = 7 | pages = 1589–608 | date = Apr 2015 | pmid = 25698114 | pmc = 4356644 | doi = 10.1016/j.jmb.2015.02.011 | url = http://www.sciencedirect.com/science/article/pii/S0022283615001059 | series = Molecular Chaperones and Protein Quality Control (Part I) }}</ref> 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|ERdj4]] and ERdj5). The functions of ERdj1 and ERdj7 are not well understood.<ref name="Behnke_2015"/>
BiP’s ATPase cycle is facilitated by its [[co-chaperone]]s, both [[Nucleotide exchange factor|nucleotide binding factors (NEFs)]], which facilitate ATP binding upon ADP release, and [[Hsp40|J proteins]], which promote ATP hydrolysis. <ref name="Behnke_2015">{{cite journal | vauthors = Behnke J, Feige MJ, Hendershot LM | title = BiP and its nucleotide exchange factors Grp170 and Sil1: mechanisms of action and biological functions | journal = Journal of Molecular Biology | volume = 427 | issue = 7 | pages = 1589–608 | date = Apr 2015 | pmid = 25698114 | pmc = 4356644 | doi = 10.1016/j.jmb.2015.02.011 | url = http://www.sciencedirect.com/science/article/pii/S0022283615001059 | series = Molecular Chaperones and Protein Quality Control (Part I) }}</ref>


== Conservation of BiP cysteines ==
== 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.<ref name="Brocchieri_2008">{{cite journal | vauthors = Brocchieri L, Conway de Macario E, Macario AJ | title = hsp70 genes in the human genome: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions | journal = BMC Evolutionary Biology | volume = 8 | issue = 1 | pages = 19 | date = 2008-01-23 | pmid = 18215318 | pmc = 2266713 | doi = 10.1186/1471-2148-8-19 | url = http://bmcevolbiol.biomedcentral.com/articles/10.1186/1471-2148-8-19 }}</ref> In the human BiP, there are two highly conserved cysteines. These cysteines have been shown to undergo [[post-translational modification]]s in both yeast and mammalian cells.<ref name="Wang_2014">{{cite journal | vauthors = Wang J, Pareja KA, Kaiser CA, Sevier CS | title = Redox signaling via the molecular chaperone BiP protects cells against endoplasmic reticulum-derived oxidative stress | journal = eLife | volume = 3 | pages = e03496 | date = 2014-07-22 | pmid = 25053742 | pmc = 4132286 | doi = 10.7554/eLife.03496 }}</ref><ref name="Wang_2016">{{cite journal | vauthors = Wang J, Sevier CS | title = Formation and Reversibility of BiP Cysteine Oxidation Facilitates Cell Survival During and Post Oxidative Stress | journal = The Journal of Biological Chemistry | date = Feb 2016 | pmid = 26865632 | doi = 10.1074/jbc.M115.694810 }}</ref><ref>{{cite journal | vauthors = 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 | title = Loss of the oxidative stress sensor NPGPx compromises GRP78 chaperone activity and induces systemic disease | journal = Molecular Cell | volume = 48 | issue = 5 | pages = 747–59 | date = Dec 2012 | pmid = 23123197 | pmc = 3582359 | doi = 10.1016/j.molcel.2012.10.007 }}</ref> In yeast cells, the N-terminus cysteine has been shown to be [[Sulfenic acid|sulfenylated]] and [[Glutathione|glutathionylated]] upon oxidative stress. Both modifications enhance BiP's ability to prevent protein aggregation.<ref name="Wang_2014" /><ref name="Wang_2016" /> In mice cells, the conserved cysteine pair forms [[disulfide bond]] upon activation of [[GPX7|GPx7]] (NPGPx). Disulfide bond enhances BiP's binding to denatured proteins.<ref>{{cite journal | vauthors = 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 | title = Loss of the oxidative stress sensor NPGPx compromises GRP78 chaperone activity and induces systemic disease | journal = Molecular Cell | volume = 48 | issue = 5 | pages = 747–59 | date = December 2012 | pmid = 23123197 | pmc = 3582359 | doi = 10.1016/j.molcel.2012.10.007 }}</ref>
BiP is highly conserved among eukaryotes, including mammals (Table 1). It is also widely expressed among all tissue types in human.<ref name="Brocchieri_2008">{{cite journal | vauthors = Brocchieri L, Conway de Macario E, Macario AJ | title = hsp70 genes in the human genome: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions | journal = BMC Evolutionary Biology | volume = 8 | issue = 1 | pages = 19 | date = 2008-01-23 | pmid = 18215318 | pmc = 2266713 | doi = 10.1186/1471-2148-8-19 | url = http://bmcevolbiol.biomedcentral.com/articles/10.1186/1471-2148-8-19 }}</ref> In the human BiP, there are two highly conserved cysteines. These cysteines have been shown to undergo [[post-translational modification]]s in both yeast and mammalian cells.<ref name="Wang_2014">{{cite journal | vauthors = Wang J, Pareja KA, Kaiser CA, Sevier CS | title = Redox signaling via the molecular chaperone BiP protects cells against endoplasmic reticulum-derived oxidative stress | journal = eLife | volume = 3 | pages = e03496 | date = 2014-07-22 | pmid = 25053742 | pmc = 4132286 | doi = 10.7554/eLife.03496 }}</ref><ref name="Wang_2016">{{cite journal | vauthors = Wang J, Sevier CS | title = Formation and Reversibility of BiP Cysteine Oxidation Facilitates Cell Survival During and Post Oxidative Stress | journal = The Journal of Biological Chemistry | date = Feb 2016 | pmid = 26865632 | doi = 10.1074/jbc.M115.694810 }}</ref><ref>{{cite journal | vauthors = 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 | title = Loss of the oxidative stress sensor NPGPx compromises GRP78 chaperone activity and induces systemic disease | journal = Molecular Cell | volume = 48 | issue = 5 | pages = 747–59 | date = Dec 2012 | pmid = 23123197 | pmc = 3582359 | doi = 10.1016/j.molcel.2012.10.007 }}</ref> In yeast cells, the N-terminus cysteine has been shown to be [[Sulfenic acid|sulfenylated]] and [[Glutathione|glutathionylated]] upon oxidative stress. Both modifications enhance BiP's ability to prevent protein aggregation.<ref name="Wang_2014" /><ref name="Wang_2016" /> In mice cells, the conserved cysteine pair forms a [[disulfide bond]] upon activation of [[GPX7|GPx7]] (NPGPx). The disulfide bond enhances BiP's binding to denatured proteins.<ref>{{cite journal | vauthors = 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 | title = Loss of the oxidative stress sensor NPGPx compromises GRP78 chaperone activity and induces systemic disease | journal = Molecular Cell | volume = 48 | issue = 5 | pages = 747–59 | date = December 2012 | pmid = 23123197 | pmc = 3582359 | doi = 10.1016/j.molcel.2012.10.007 }}</ref>


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== Clinical significance ==
== Clinical significance ==


=== Immunological diseases ===
=== [[Autoimmune disease]] ===


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.<ref name="pmid15245751">{{cite journal | vauthors = Panayi GS, Corrigall VM, Henderson B | title = Stress cytokines: pivotal proteins in immune regulatory networks; Opinion | journal = Current Opinion in Immunology | volume = 16 | issue = 4 | pages = 531–4 | date = Aug 2004 | pmid = 15245751 | doi = 10.1016/j.coi.2004.05.017 }}</ref> Specifically, it feeds anti-inflammatory and pro-resolutory signals into immune networks, thus helping to resolve inflammation.<ref name="pmid21671907">{{cite journal | vauthors = Shields AM, Panayi GS, Corrigall VM | title = Resolution-associated molecular patterns (RAMP): RAMParts defending immunological homeostasis? | journal = Clinical and Experimental Immunology | volume = 165 | issue = 3 | pages = 292–300 | date = Sep 2011 | pmid = 21671907 | pmc = 3170978 | doi = 10.1111/j.1365-2249.2011.04433.x }}</ref>
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.<ref name="pmid15245751">{{cite journal | vauthors = Panayi GS, Corrigall VM, Henderson B | title = Stress cytokines: pivotal proteins in immune regulatory networks; Opinion | journal = Current Opinion in Immunology | volume = 16 | issue = 4 | pages = 531–4 | date = Aug 2004 | pmid = 15245751 | doi = 10.1016/j.coi.2004.05.017 }}</ref> Specifically, it feeds anti-inflammatory and pro-resolutory signals into immune networks, thus helping to resolve [[inflammation]].<ref name="pmid21671907">{{cite journal | vauthors = Shields AM, Panayi GS, Corrigall VM | title = Resolution-associated molecular patterns (RAMP): RAMParts defending immunological homeostasis? | journal = Clinical and Experimental Immunology | volume = 165 | issue = 3 | pages = 292–300 | date = Sep 2011 | pmid = 21671907 | pmc = 3170978 | doi = 10.1111/j.1365-2249.2011.04433.x }}</ref> 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 [[monocyte]]s, downregulate critical molecules involved in [[T-lymphocyte]] activation, and modulate the differentiation pathway of monocytes into [[dendritic cell]]s.<ref name="pmid15077298">{{cite journal | vauthors = Corrigall VM, Bodman-Smith MD, Brunst M, Cornell H, Panayi GS | title = 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 | journal = Arthritis and Rheumatism | volume = 50 | issue = 4 | pages = 1164–71 | date = Apr 2004 | pmid = 15077298 | doi = 10.1002/art.20134 }}</ref><ref name="pmid19740378 ">{{cite journal | vauthors = Corrigall VM, Vittecoq O, Panayi GS | title = Binding immunoglobulin protein-treated peripheral blood monocyte-derived dendritic cells are refractory to maturation and induce regulatory T-cell development | journal = Immunology | volume = 128 | issue = 2 | pages = 218–26 | date = Oct 2009 | pmid = 19740378 | pmc = 2767311 | doi = 10.1111/j.1365-2567.2009.03103.x }}</ref>

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 [[interleukin 10|IL-10]], [[interleukin 1 receptor antagonist|IL-1Ra]], and soluble [[tumor necrosis factor receptor|TNFR]].<ref name="pmid15077298">{{cite journal | vauthors = Corrigall VM, Bodman-Smith MD, Brunst M, Cornell H, Panayi GS | title = 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 | journal = Arthritis and Rheumatism | volume = 50 | issue = 4 | pages = 1164–71 | date = Apr 2004 | pmid = 15077298 | doi = 10.1002/art.20134 }}</ref> Furthermore, it downregulates critical molecules involved in [[T-lymphocyte]] activation such as [[HLA-DR]] and [[CD86]].<ref name="pmid15077298" /> 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.<ref name="pmid19740378 ">{{cite journal | vauthors = Corrigall VM, Vittecoq O, Panayi GS | title = Binding immunoglobulin protein-treated peripheral blood monocyte-derived dendritic cells are refractory to maturation and induce regulatory T-cell development | journal = Immunology | volume = 128 | issue = 2 | pages = 218–26 | date = Oct 2009 | pmid = 19740378 | pmc = 2767311 | doi = 10.1111/j.1365-2567.2009.03103.x }}</ref>


The potent immunomodulatory activities of BiP/GRP78 have also been demonstrated in animal models of autoimmune disease including [[collagen-induced arthritis]],<ref name="pmid11160188 ">{{cite journal | vauthors = 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 | title = The human endoplasmic reticulum molecular chaperone BiP is an autoantigen for rheumatoid arthritis and prevents the induction of experimental arthritis | journal = Journal of Immunology | volume = 166 | issue = 3 | pages = 1492–8 | date = Feb 2001 | pmid = 11160188 | doi = 10.4049/jimmunol.166.3.1492 }}</ref> 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.<ref name="pmid16508967 ">{{cite journal | vauthors = Brownlie RJ, Myers LK, Wooley PH, Corrigall VM, Bodman-Smith MD, Panayi GS, Thompson SJ | title = 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 | journal = Arthritis and Rheumatism | volume = 54 | issue = 3 | pages = 854–63 | date = Mar 2006 | pmid = 16508967 | doi = 10.1002/art.21654 }}</ref>
The potent immunomodulatory activities of BiP/GRP78 have also been demonstrated in animal models of autoimmune disease including [[collagen-induced arthritis]],<ref name="pmid11160188 ">{{cite journal | vauthors = 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 | title = The human endoplasmic reticulum molecular chaperone BiP is an autoantigen for rheumatoid arthritis and prevents the induction of experimental arthritis | journal = Journal of Immunology | volume = 166 | issue = 3 | pages = 1492–8 | date = Feb 2001 | pmid = 11160188 | doi = 10.4049/jimmunol.166.3.1492 }}</ref> 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.<ref name="pmid16508967 ">{{cite journal | vauthors = Brownlie RJ, Myers LK, Wooley PH, Corrigall VM, Bodman-Smith MD, Panayi GS, Thompson SJ | title = 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 | journal = Arthritis and Rheumatism | volume = 54 | issue = 3 | pages = 854–63 | date = Mar 2006 | pmid = 16508967 | doi = 10.1002/art.21654 }}</ref>


=== Heart diseases ===
=== [[Cardiovascular disease]] ===

Upregulation of BiP has been associated with ER stress-induced cardiac dysfunction and [[dilated cardiomyopathy]].<ref>{{cite journal|last1=Roe|first1=ND|last2=Ren|first2=J|title=Oxidative activation of Ca(2+)/calmodulin-activated kinase II mediates ER stress-induced cardiac dysfunction and apoptosis.|journal=American journal of physiology. Heart and circulatory physiology|date=15 March 2013|volume=304|issue=6|pages=H828-39|pmid=23316062}}</ref><ref>{{cite journal|last1=Okada|first1=K|last2=Minamino|first2=T|last3=Tsukamoto|first3=Y|last4=Liao|first4=Y|last5=Tsukamoto|first5=O|last6=Takashima|first6=S|last7=Hirata|first7=A|last8=Fujita|first8=M|last9=Nagamachi|first9=Y|last10=Nakatani|first10=T|last11=Yutani|first11=C|last12=Ozawa|first12=K|last13=Ogawa|first13=S|last14=Tomoike|first14=H|last15=Hori|first15=M|last16=Kitakaze|first16=M|title=Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis.|journal=Circulation|date=10 August 2004|volume=110|issue=6|pages=705-12|pmid=15289376}}</ref> BiP can also suppress the development of [[atherosclerosis]] through alleviating [[homocysteine]]-induced ER stress, preventing apoptosis of [[vascular]] [[endothelial cell]]s, 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]].<ref name=pmid17481612>{{cite journal|last1=Ni|first1=M|last2=Lee|first2=AS|title=ER chaperones in mammalian development and human diseases.|journal=FEBS letters|date=31 July 2007|volume=581|issue=19|pages=3641-51|pmid=17481612}}</ref>

⚫
Some [[anticancer drug]]s, such as [[proteasome inhibitor]]s, have been associated with heart failure complications. In rat [[neonatal]] cardiomyocytes, overexpression of BiP attenuates cardiomyocyte death induced by proteasome inhibition.<ref>{{cite journal | vauthors = Fu HY, Minamino T, Tsukamoto O, Sawada T, Asai M, Kato H, Asano Y, Fujita M, Takashima S, Hori M, Kitakaze M | title = Overexpression of endoplasmic reticulum-resident chaperone attenuates cardiomyocyte death induced by proteasome inhibition | journal = Cardiovascular Research | volume = 79 | issue = 4 | pages = 600–10 | date = Sep 2008 | pmid = 18508854 | doi = 10.1093/cvr/cvn128}}</ref>

=== [[Neurodegenerative disease]] ===


As an ER chaperone protein, BiP prevents [[neuronal cell]] death induced by ER stress by correcting misfolded proteins.<ref>{{cite journal|last1=Zhao|first1=L|last2=Longo-Guess|first2=C|last3=Harris|first3=BS|last4=Lee|first4=JW|last5=Ackerman|first5=SL|title=Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP.|journal=Nature genetics|date=September 2005|volume=37|issue=9|pages=974-9|pmid=16116427}}</ref><ref>{{cite journal|last1=Anttonen|first1=AK|last2=Mahjneh|first2=I|last3=Hämäläinen|first3=RH|last4=Lagier-Tourenne|first4=C|last5=Kopra|first5=O|last6=Waris|first6=L|last7=Anttonen|first7=M|last8=Joensuu|first8=T|last9=Kalimo|first9=H|last10=Paetau|first10=A|last11=Tranebjaerg|first11=L|last12=Chaigne|first12=D|last13=Koenig|first13=M|last14=Eeg-Olofsson|first14=O|last15=Udd|first15=B|last16=Somer|first16=M|last17=Somer|first17=H|last18=Lehesjoki|first18=AE|title=The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone.|journal=Nature genetics|date=December 2005|volume=37|issue=12|pages=1309-11|pmid=16282978}}</ref> Moreover, a chemical inducer of BiP, named BIX, reduced cerebral infarction in cerebral [[ischemic]] mice <ref name="pmid18049481">{{cite journal | vauthors = Kudo T, Kanemoto S, Hara H, Morimoto N, Morihara T, Kimura R, Tabira T, Imaizumi K, Takeda M | title = A molecular chaperone inducer protects neurons from ER stress | journal = Cell Death and Differentiation | volume = 15 | issue = 2 | pages = 364–75 | date = Feb 2008 | pmid = 18049481 | doi = 10.1038/sj.cdd.4402276 }}</ref>.[45] Conversely, enhanced BiP chaperone function has been strongly implicated in [[Alzheimer’s disease]].<ref name=pmid17481612/><ref name=pmid25546329>{{cite journal|last1=Booth|first1=L|last2=Roberts|first2=JL|last3=Cash|first3=DR|last4=Tavallai|first4=S|last5=Jean|first5=S|last6=Fidanza|first6=A|last7=Cruz-Luna|first7=T|last8=Siembiba|first8=P|last9=Cycon|first9=KA|last10=Cornelissen|first10=CN|last11=Dent|first11=P|title=GRP78/BiP/HSPA5/Dna K is a universal therapeutic target for human disease.|journal=Journal of cellular physiology|date=July 2015|volume=230|issue=7|pages=1661-76|pmid=25546329}}</ref>.
BiP is recognized by heart infiltrating and [[Peripheral T cell lymphoma|peripheral T cells]] from [[Rheumatic heart disease|rheumatic heart disease (RHD)]] patients. RHD is the major manifestation of RF, is characterized by [[inflammation]] of [[heart valve]]s and [[myocardium]].Identification of BiP as the target antigen suggests BiP may be involved in the [[autoimmune]] reactions that leads to valve damage.<ref>{{cite journal | vauthors = Faé KC, Diefenbach da Silva D, Bilate AM, Tanaka AC, Pomerantzeff PM, Kiss MH, Silva CA, Cunha-Neto E, Kalil J, Guilherme L | title = 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 = Journal of Autoimmunity | volume = 31 | issue = 2 | pages = 136–41 | date = Sep 2008 | pmid = 18541406 | doi = 10.1016/j.jaut.2008.04.023 }}</ref>


=== [[Metabolic disease]] ===
⚫
As a novel class of [[anticancer agents]], [[Proteasome inhibitor]]s trigger heart failure through elevation of [[ER stress]].<ref>{{cite journal | vauthors = 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 | title = Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis | journal = Circulation | volume = 110 | issue = 6 | pages = 705–12 | date = Aug 2004 | pmid = 15289376 | doi = 10.1161/01.CIR.0000137836.95625.D4 }}</ref> In rat [[neonatal]] cardiomyocytes, overexpression of BiP attenuates cardiomyocyte death induced by proteasome inhibition.<ref>{{cite journal | vauthors = Fu HY, Minamino T, Tsukamoto O, Sawada T, Asai M, Kato H, Asano Y, Fujita M, Takashima S, Hori M, Kitakaze M | title = Overexpression of endoplasmic reticulum-resident chaperone attenuates cardiomyocyte death induced by proteasome inhibition | journal = Cardiovascular Research | volume = 79 | issue = 4 | pages = 600–10 | date = Sep 2008 | pmid = 18508854 | doi = 10.1093/cvr/cvn128}}</ref>
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.<ref>{{cite journal|last1=Scheuner|first1=D|last2=Vander Mierde|first2=D|last3=Song|first3=B|last4=Flamez|first4=D|last5=Creemers|first5=JW|last6=Tsukamoto|first6=K|last7=Ribick|first7=M|last8=Schuit|first8=FC|last9=Kaufman|first9=RJ|title=Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis.|journal=Nature medicine|date=July 2005|volume=11|issue=7|pages=757-64|pmid=15980866}}</ref>


=== [[Infectious disease]] ===
=== BiP inhibitors and enhancers ===


[[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 [[Super bug (bacteria)|superbug]] [[Strain (biology)|strains]] of [[Neisseria gonorrhoeae]] to several standard-of-care [[antibiotics]].<ref name=pmid25546329/> Meanwhile, a [[virulent strain]] of [[Verotoxin-producing Escherichia coli|Shiga toxigenic Escherichia coli]] undermines host cell survival by producing [[AB5 toxin]] to inhibit host BiP.<ref name=pmid17481612/> In contrast, [[virus]]es 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.<ref name=pmid25546329/><ref>{{cite journal|last1=Rathore|first1=AP|last2=Ng|first2=ML|last3=Vasudevan|first3=SG|title=Differential unfolded protein response during Chikungunya and Sindbis virus infection: CHIKV nsP4 suppresses eIF2α phosphorylation.|journal=Virology journal|date=28 January 2013|volume=10|pages=36|pmid=23356742}}</ref>
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.<ref name="pmid23807168">{{cite journal | vauthors = Martin S, Lamb HK, Brady C, Lefkove B, Bonner MY, Thompson P, Lovat PE, Arbiser JL, Hawkins AR, Redfern CP | title = Inducing apoptosis of cancer cells using small-molecule plant compounds that bind to GRP78 | journal = British Journal of Cancer | volume = 109 | issue = 2 | pages = 433–43 | date = Jul 2013 | pmid = 23807168 | doi = 10.1038/bjc.2013.325 }}</ref> OSU-03012 (AR-12), The BiP inhibitor [[OSU-03012|OSU-03012 (AR-12)]], a derivative of the drug [[Celebrex|celecoxib (Celebrex)]], interacting with [[Sildenafil|sildenafil (Viagra)]] or [[Tadalafil|tadalafil (Cialis)]] can rapidly reduce BiP levels in eukaryotes.<ref>{{cite journal | vauthors = Booth L, Roberts JL, Cash DR, Tavallai S, Jean S, Fidanza A, Cruz-Luna T, Siembiba P, Cycon KA, Cornelissen CN, Dent P | title = GRP78/BiP/HSPA5/Dna K is a universal therapeutic target for human disease | journal = Journal of Cellular Physiology | volume = 230 | issue = 7 | pages = 1661–76 | date = Jul 2015 | pmid = 25546329 | pmc = 4402027 | doi = 10.1002/jcp.24919 }}</ref> Inducers of BiP were also found including, BiP inducer X (BIX) was identified in a screen for compounds that induce BiP expression.<ref name="pmid18049481">{{cite journal | vauthors = Kudo T, Kanemoto S, Hara H, Morimoto N, Morihara T, Kimura R, Tabira T, Imaizumi K, Takeda M | title = A molecular chaperone inducer protects neurons from ER stress | journal = Cell Death and Differentiation | volume = 15 | issue = 2 | pages = 364–75 | date = Feb 2008 | pmid = 18049481 | doi = 10.1038/sj.cdd.4402276 }}</ref>


== References ==
== References ==

Revision as of 20:09, 2 June 2016

HSPA5
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesHSPA5, BIP, GRP78, HEL-S-89n, MIF2, Binding immunoglobulin protein, heat shock protein family A (Hsp70) member 5, GRP78/Bip
External IDsOMIM: 138120; MGI: 95835; HomoloGene: 3908; GeneCards: HSPA5; OMA:HSPA5 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3309

14828

Ensembl

ENSG00000044574

ENSMUSG00000026864

UniProt

P11021

P20029

RefSeq (mRNA)

NM_005347

NM_001163434
NM_022310

RefSeq (protein)

NP_005338

NP_001156906
NP_071705

Location (UCSC)Chr 9: 125.23 – 125.24 MbChr 2: 34.66 – 34.67 Mb
PubMed search[3][4]
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.[5][6]

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.[7]

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).[8][9][10] 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.[11][12][13] An inter-domain linker connects NBD and SBD, favoring the irformation of an NBD–SBD interface.[7]

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.[14][15][16] The ATPase cycle can be synergistically enhanced by protein disulfide isomerase (PDI),[17] and its cochaperones.[18]

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.[6] The level of BiP is strongly correlated with the amount of secretory proteins (e.g. IgG) within the ER.[19]

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.[9]

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-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.[20]

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.[21][22][23]

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.[24] ATPase mutants (including allosteric mutants) of BiP have been shown to significantly slow down the degradation rate of CPY*.[25][26]

UPR pathway

BiP is both a target of the ER stress response, or UPR, and an essential regulator of the UPR pathway.[27][28] During ER stress, BiP dissociates from the three transducers (IRE1, PERK, and ATF6), effectively activating their respective UPR pathways.[29] As a UPR target gene product, BiP is upregulated when UPR transcription factors associate with the UPR element in BiP’s DNA promoter region.[30]

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. [18]

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.[31] 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.[32][33][34] 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.[32][33] 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.[35]

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.[36] Specifically, it feeds anti-inflammatory and pro-resolutory signals into immune networks, thus helping to resolve inflammation.[37] 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.[38][39]

The potent immunomodulatory activities of BiP/GRP78 have also been demonstrated in animal models of autoimmune disease including collagen-induced arthritis,[40] 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.[41]

Cardiovascular disease

Upregulation of BiP has been associated with ER stress-induced cardiac dysfunction and dilated cardiomyopathy.[42][43] BiP can also 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.[44]

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.[45]

Neurodegenerative disease

As an ER chaperone protein, BiP prevents neuronal cell death induced by ER stress by correcting misfolded proteins.[46][47] Moreover, a chemical inducer of BiP, named BIX, reduced cerebral infarction in cerebral ischemic mice [48].[45] Conversely, enhanced BiP chaperone function has been strongly implicated in Alzheimer’s disease.[44][49].

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.[50]

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.[49] Meanwhile, a virulent strain of Shiga toxigenic Escherichia coli undermines host cell survival by producing AB5 toxin to inhibit host BiP.[44] 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.[49][51]

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External links

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