Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P11021 (BiP)
 2,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endoplasmic reticulum (ER)-localized chaperone protein, GRP78-BiP, is involved in the folding and oligomerization of secreted and membrane proteins, including the simian virus 5 hemagglutinin-neuraminidase (HN) glycoprotein. To understand this interaction better, we have constructed a series of HN mutants in which specific portions of the extracytoplasmic domain have been deleted. Analysis of these mutant polypeptides expressed in CV-1 cells have indicated that GRP78-BiP binds to selective sequences in HN and that there exists more than a single site of interaction. Mutant polypeptides have been characterized that are competent and incompetent for association with GRP78-BiP. These mutants have been used to show that the induction of GRP78-BiP synthesis due to the presence of nonnative protein molecules in the ER is dependent on GRP78-BiP complex formation with its substrates. These studies have implications for the function of the GRP78-BiP protein and the mechanism by which the gene is regulated.
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PMID:Analysis in vivo of GRP78-BiP/substrate interactions and their role in induction of the GRP78-BiP gene. 155 Sep 58

The influenza virus neuraminidase (NA), a type II transmembrane glycoprotein, is expressed at the surface of infected cells and is a major structural component of the virion. The kinetics of biosynthesis of NA, including modification of N-linked sugar chains, association with GRP78-BiP, oligomerization, and transport to the cell surface, were examined in A/WSN/33 influenza-infected BHK cells. Prior to gaining endoglycosidase H (endo H) resistance, NA was found to transiently associate with GRP78-BiP (t1/2 approximately 5 min). The protein was synthesized as a monomer and within 10 min a significant fraction of it was chased into dimers and tetramers with a t1/2 approximately 15 to 20 min before endo H resistance was acquired suggesting that oligomerization took place in the endoplasmic reticulum. WSN NA remained completely endo H sensitive up to 15 min after synthesis, acquired partial resistance to endo H between 15 and 30 min (t1/2 approximately 25 min) after synthesis and exhibited heterogeneity in endo H-resistant forms. NA was first detected at the cell surface 30 min after synthesis, increased to a maximum at 1 hr, after which it decreased, presumably due to incorporation into virions. The results on the biosynthesis of NA, a type II protein for which the three-dimensional structure is known, will be useful in structure/function and virion assembly studies.
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PMID:Synthesis and processing of the influenza virus neuraminidase, a type II transmembrane glycoprotein. 158 34

SEC63 encodes a protein required for secretory protein translocation into the endoplasmic reticulum (ER) of Saccharomyces cerevisiae (J. A. Rothblatt, R. J. Deshaies, S. L. Sanders, G. Daum, and R. Schekman, J. Cell Biol. 109:2641-2652, 1989). Antibody directed against a recombinant form of the protein detects a 73-kDa polypeptide which, by immunofluorescence microscopy, is localized to the nuclear envelope-ER network. Cell fractionation and protease protection experiments confirm the prediction that Sec63p is an integral membrane protein. A series of SEC63-SUC2 fusion genes was created to assess the topology of Sec63p within the ER membrane. The largest hybrid proteins are unglycosylated, suggesting that the carboxyl terminus of Sec63p faces the cytosol. Invertase fusion to a loop in Sec63p that is flanked by two putative transmembrane domains produces an extensively glycosylated hybrid protein. This loop, which is homologous to the amino terminus of the Escherichia coli heat shock protein, DnaJ, is likely to face the ER lumen. By analogy to the interaction of the DnaJ and Hsp70-like DnaK proteins in E. coli, the DnaJ loop of Sec63p may recruit luminal Hsp70 (BiP/GRP78/Kar2p) to the translocation apparatus. Mutations in two highly conserved positions of the DnaJ loop and short deletions of the carboxyl terminus inactivate Sec63p activity. Sec63p associates with several other proteins, including Sec61p, a 31.5-kDa glycoprotein, and a 23-kDa protein, and together with these proteins may constitute part of the polypeptide translocation apparatus. A nonfunctional DnaJ domain mutant allele does not interfere with the formation of the Sec63p/Sec61p/gp31.5/p23 complex.
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PMID:Topology and functional domains of Sec63p, an endoplasmic reticulum membrane protein required for secretory protein translocation. 162 Jan 30

Immunoglobulin heavy chain binding protein (BiP, GRP 78) coprecipitates with soluble and membrane-associated variants of the T-cell antigen receptor alpha chain (TCR-alpha) which are stably retained within the ER. Chelation of Ca2+ during solubilization of cells leads to the dissociation of BiP from the TCR-alpha variants, which is dependent upon the availability of Mg2+ and hydrolyzable ATP; this suggests that Ca2+ levels can serve to modulate the association/dissociation of these proteins with BiP. In vivo treatment of cells expressing either the soluble or membrane-anchored TCR-alpha variants with the Ca2+ ionophore, A23187, or an inhibitor of an ER Ca(2+)-ATPase, thapsigargin, or the membrane-permeant Ca2+ chelator BAPTA-AM, results in the redistribution of these proteins out of the ER and their subsequent secretion or cell surface expression. Under the same assay conditions, no movement of BiP out of the ER is observed. Taken together, these observations indicate that decreased Ca2+ levels result in the dissociation of a protein bound to BiP, leading to its release from ER retention. These data suggest that the intracellular fate of newly synthesized proteins stably associated with BiP can be regulated by Ca2+ levels in the ER.
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PMID:Regulating the retention of T-cell receptor alpha chain variants within the endoplasmic reticulum: Ca(2+)-dependent association with BiP. 164 96

GRP78/BiP resides in the lumen of the endoplasmic reticulum (ER), a major site of Ca2+ sequestration and early protein processing. Agents, such as ionophore A23187, that mobilize sequestered ER Ca2+ suppress translational initiation within minutes and induce GRP78 within 1-3 h accompanied by development of translational tolerance to the inhibitor. Accommodation is prevented by actinomycin D and reduced by antisense oligonucleotides directed against GRP78 mRNA. In GH3 cells, optimal induction of GRP78 and translational accommodation depended on cAMP elevation and phorbol ester. GRP78 mRNA was induced 3-6-fold with A23187 alone as compared with 12-20-fold with ionophore plus cAMP-elevating agent and phorbol ester, but was not markedly induced without A23187. GRP78 gene transcription in nuclei isolated from A23187-treated cells was increased 2-4-fold by cAMP and phorbol ester. A nucleotide sequence homologous to the cAMP-responsive element consensus potentially exists in the promoter region of the GRP78 gene. GRP78 mRNA in ionophore-treated cells was largely associated with mono- and polysomal fractions rather than ribonuclear protein particles, a distribution different from actin and tubulin mRNAs. While polysomal content increased in cells undergoing translational recovery, cAMP and phorbol esters did not affect GRP78 mRNA stability. Translational accommodation in ionophore-treated GH3 cells is proposed to involve enhanced transcription of GRP78 mRNA promoted by cAMP/phorbol ester in conjunction with preferential polysomal loading of the message.
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PMID:Stimulation of GRP78 gene transcription by phorbol ester and cAMP in GH3 pituitary cells. The accommodation of protein synthesis to chronic deprivation of intracellular sequestered calcium. 165 95

The immunoglobulin heavy chain binding protein BiP/GRP78 is post-translationally modified by phosphorylation and ADP ribosylation. In cells induced to synthesize higher levels of BiP, either due to the accumulation of nontransported proteins or to glucose starvation, both BiP phosphorylation and ADP ribosylation are reduced. BiP bound to other proteins is unmodified, suggesting that both phosphorylation and ADP ribosylation are restricted to the unbound BiP pool. In the present study, both modifications were further characterized in terms of their stability, the pool of BiP that harbored these modifications, and the relationship between the modified and unmodified forms of BiP. While levels of BiP synthesis vary according to the physiological state of a cell, we found that both induced and uninduced cells contain similar amounts of free BiP. However, free BiP in uninduced cells was found primarily in an aggregated state, whereas in cells that accumulate nontransported proteins, it was predominantly monomeric. Both phosphorylation and ADP ribosylation were restricted to the aggregated form of free BiP. These post-translational modifications occurred upon release of BiP from associated proteins, and could be reversed upon induction of BiP synthesis. Therefore, BiP exists either (1) complexed to other proteins, (2) as a free unmodified monomer, or (3) as free modified aggregates. Our data suggest that BiP can be interconverted from one state to another, and that the various forms are functionally distinct.
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PMID:Interconversion of three differentially modified and assembled forms of BiP. 174 Jan 16

cDNAs of fibrinogen A alpha and gamma chains were individually subcloned into a eukaryotic expression vector by using the polymerase chain reaction. Triple cotransfection into COS cells of the two plasmids together with a B beta chain expression plasmid, constructed as described previously (Danishefsky, K.J., Hartwig, R., Banerjee, D., and Redman, C. (1990) Biochim. Biophys. Acta 1048, 202-208), resulted in the secretion of complete fibrinogen into the media and the formation of four additional intracellular complexes which we also showed to be present in the hepatocyte cell line Hep 3B. The complexes, which have Mr = 232, 150, 135, and 128 (x 10(-3) conform with the Mr expected for A alpha B beta gamma 2, B beta gamma 2 and gamma 3, respectively. A A mechanism of assembly is proposed based on the assumption that all these complexes are precursors of complete fibrinogen. Each of the expressed fibrinogen chains in transfected COS cells interacts noncovalently with binding protein (BiP, GRP 78), but not to the same extent; gamma chain binds less BiP than the A alpha and B beta chains. Assembly of fibrinogen is not absolutely required for its secretion. In addition to complete fibrinogen, the conditioned media of hepatocytes and of transfected COS cells contained free A alpha, free gamma, and two of the above-mentioned complexes, A alpha gamma 2 and A alpha B beta gamma 2.
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PMID:Studies on the assembly and secretion of fibrinogen. 182 7

The heat shock/stress response is characterized by the induction of several highly evolutionarily conserved proteins during thermal stress, chemical stress, or glucose starvation. It has recently been recognized that members of the stress protein family are synthesized constitutively and subserve functions that are critical to protein folding during intracellular transport. In this study we examined the expression of heat shock/stress proteins in human mononuclear phagocytes, cells dependent on intracellular transport for Ag processing, Ag presentation, generation of reactive oxygen intermediates, and secretion of proinflammatory and antiinflammatory polypeptides. The results indicate that there are distinct patterns in expression of individual members of the highly homologous SP70, SP90, and ubiquitin gene families during different stress states. There is a marked increase in expression of the heat-inducible form of SP70 and SP90 in human monocytes during heat shock. Expression of GRP 78/BiP and GRP 94 increases predominantly during glucose starvation but also increases during heat shock. Ubiquitin gene expression increases during both heat shock and glucose starvation. There is no change in synthesis of the constitutive form of SP 70 or of the ubiquitin activating enzyme E1 during heat shock or glucose starvation. Synthesis of the constitutive form of SP 70 and novel SP 90-like polypeptides increase during endotoxin-mediated inflammatory activation. One intracellular transport process of the mononuclear phagocyte, secretion of specific proinflammatory and antiinflammatory polypeptides, is affected by glucose starvation and by heat shock.
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PMID:Expression of stress proteins in human mononuclear phagocytes. 188 Apr 18

A detailed kinetic and quantitative analysis of the early and late biosynthetic events undergone by the human immunodeficiency virus type 1 envelope protein expressed by a recombinant vaccinia virus was performed. Early folding events that occurred in the endoplasmic reticulum included disulfide bond formation (t1/2 approximately 10 min), folding of envelope protein into a form competent to bind CD4 (t1/2 approximately 15 min), and specific and transient association and dissociation with GRP78-BiP (t1/2 approximately 25 min). After initial folding, envelope protein monomers formed noncovalently associated dimers with high efficiency (t1/2 approximately 30 min). Studies with brefeldin A, a compound that inhibits endoplasmic reticulum-to-Golgi transport, suggested that assembly occurred in the endoplasmic reticulum while cleavage of gp160 into gp120/gp41 subunits occurred in a post-endoplasmic reticulum compartment. Transport to the Golgi was monitored by modification of N-linked sugars to forms partially resistant to endoglycosidase H. The kinetics of endoglycosidase H resistance were nearly identical to the kinetics of gp160 cleavage (t1/2 approximately 80 min). Cleavage efficiency was strongly cell type dependent, ranging from 13 to 70%. By contrast, approximately 50% of the gp120 generated by the cleavage event was shed (t1/2 approximately 120 min) regardless of the cell type used. The results are discussed in terms of the overall biosynthetic pathway of the envelope protein and provide a framework with which to assess the effects of mutations on structure and function.
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PMID:Folding, interaction with GRP78-BiP, assembly, and transport of the human immunodeficiency virus type 1 envelope protein. 190 May 40

The cellular glucose-regulated protein GRP78-BiP is a member of the HSP70 stress family of gene products, and the protein is a resident component of the endoplasmic reticulum, where it is thought to play a role in the folding and oligomerization of secretory and membrane-bound proteins. GRP78-BiP also binds to malfolded proteins, and this may be one mechanism for preventing their intracellular transport. An induction in synthesis of the GRP78-BiP protein occurs in cells infected with paramyxoviruses (R. W. Peluso, R. A. Lamb, and P. W. Choppin, Proc. Natl. Acad. Sci. USA 75:6120-6124, 1978). We have studied the expression and activity of the GRP78-BiP gene and synthesis of the GRP78-BiP protein during infection with the paramyxovirus simian virus 5 (SV5). We wished to identify the viral component capable of causing activation of GRP78-BiP since GRP78-BiP interacts specifically and transiently with the SV5 hemagglutinin-neuraminidase (HN) glycoprotein during HN folding (D. T. W. Ng, R. E. Randall, and R. A. Lamb, J. Cell Biol. 109:3273-3289, 1989). Expression of cDNAs of the SV5 wild-type HN glycoprotein and a mutant form of HN that is malfolded but not the SV5 F glycoprotein or SV5 cytoplasmic proteins P, V, and M caused increased amounts of GRP78-BiP mRNA to accumulate, as detected by nuclease S1 protection assays. As unfolded or malfolded forms of HN cannot be detected to accumulate during SV5 infection, the data suggest that the flux of HN through the ER in SV5-infected cells can cause activation of GRP78-BiP transcription.
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PMID:Flux of the paramyxovirus hemagglutinin-neuraminidase glycoprotein through the endoplasmic reticulum activates transcription of the GRP78-BiP gene. 204 Oct 85


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