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)

GRP94 is a molecular chaperone that carries immunologically relevant peptides from cell to cell, transferring them to major histocompatibility proteins for presentation to T cells. Here we examine the binding of several peptides to recombinant GRP94 and study the regulation and site of peptide binding. We show that GRP94 contains a peptide-binding site in its N-terminal 355 amino acids. A number of peptides bind to this site with low on- and off-rates and with specificity that is distinct from that of another endoplasmic reticulum chaperone, BiP/GRP78. Binding to the N-terminal fragment is sufficient to account for the peptide binding activity of the entire molecule. Peptide binding is inhibited by radicicol, a known inhibitor of the chaperone activities of HSP90-family proteins. However, the peptide-binding site is distinct from the radicicol-binding pocket, because both can bind to the N-terminal fragment simultaneously. Furthermore, peptide binding does not cause the same conformational change as does binding of radicicol. When the latter binds to the N-terminal domain, it induces a conformational change in the downstream, acidic domain of GRP94, as measured by altered gel mobility and loss of an antibody epitope. These results relate the peptide-binding activity of GRP94 to its other function as a chaperone.
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PMID:Radicicol-sensitive peptide binding to the N-terminal portion of GRP94. 1218 40

Efficient protein folding and trafficking are essential for high-level production of secretory proteins. Slow folding or misfolding of proteins can lead to secretory bottlenecks that reduce productivity. We previously examined the expression of a hyperthermophilic tetramer Pyrococcus furiosus beta-glucosidase in the yeast Saccharomyces cerevisiae. A secretory bottleneck was found in the endoplasmic reticulum, presumably due to beta-glucosidase misfolding. By increasing expression temperature from 30 degrees C up to 40 degrees C, secretion yields increased by as much as 440% per cell to greater than 100 mg/L at 37 degrees C. We examined the effect of temperature on beta-glucosidase folding and secretion and determined that increased expression temperature decreased intracellularly retained, insoluble beta-glucosidase. Likewise, stress on the cell caused by beta-glucosidase expression was found to be greatly reduced at 37 degrees C compared to 30 degrees C. Levels of the abundant endoplasmic reticulum chaperone, BiP, were relatively unchanged at these temperatures during heterologous expression. Using cycloheximide to inhibit new protein synthesis, we determined that the increase in secretion is likely due to the effect of temperature on the beta-glucosidase itself rather than the cell's response to elevated temperatures. We believe that this is the first evidence of in vivo effects of temperature on the secretion of hyperthermophilic proteins.
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PMID:Elevated expression temperature in a mesophilic host results in increased secretion of a hyperthermophilic enzyme and decreased cell stress. 1611 28

The conserved protein-conducting channel, referred to as the Sec61 channel in eukaryotes or the SecY channel in eubacteria and archaea, translocates proteins across cellular membranes and integrates proteins containing hydrophobic transmembrane segments into lipid bilayers. Structural studies illustrate how the protein-conducting channel accomplishes these tasks. Three different mechanisms, each requiring a different set of channel binding partners, are employed to move polypeptide substrates: The ribosome feeds the polypeptide chain directly into the channel, a ratcheting mechanism is used by the eukaryotic endoplasmic reticulum chaperone BiP, and a pushing mechanism is utilized by the bacterial ATPase SecA. We review these translocation mechanisms, relating biochemical and genetic observations to the structures of the protein-conducting channel and its binding partners.
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PMID:Protein translocation by the Sec61/SecY channel. 1621 6

The endoplasmic reticulum chaperone BiP, in addition to its many important intracellular functions, has anti-inflammatory and immunomodulatory properties when present in the extracellular environment by the stimulation of an anti-inflammatory gene programme from human monocytes and by the development of T-cells that secrete regulatory cytokines such as interleukin-10 and interleukin-4. It can both prevent as well as treat ongoing collagen-induced arthritis. It is, therefore, a potential new biologic therapy for rheumatoid arthritis.
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PMID:BiP regulates autoimmune inflammation and tissue damage. 1643 46

AB5 toxins are produced by pathogenic bacteria and consist of enzymatic A subunits that corrupt essential eukaryotic cell functions, and pentameric B subunits that mediate uptake into the target cell. AB5 toxins include the Shiga, cholera and pertussis toxins and a recently discovered fourth family, subtilase cytotoxin, which is produced by certain Shiga toxigenic strains of Escherichia coli. Here we show that the extreme cytotoxicity of this toxin for eukaryotic cells is due to a specific single-site cleavage of the essential endoplasmic reticulum chaperone BiP/GRP78. The A subunit is a subtilase-like serine protease; structural studies revealed an unusually deep active-site cleft, which accounts for its exquisite substrate specificity. A single amino-acid substitution in the BiP target site prevented cleavage, and co-expression of this resistant protein protected transfected cells against the toxin. BiP is a master regulator of endoplasmic reticulum function, and its cleavage by subtilase cytotoxin represents a previously unknown trigger for cell death.
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PMID:AB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP. 1702 74

Cancer cells adapt to chronic stress in the tumor microenvironment by inducing the expression of GRP78/BiP, a major endoplasmic reticulum chaperone with Ca(2+)-binding and antiapoptotic properties. GRP78 promotes tumor proliferation, survival, metastasis, and resistance to a wide variety of therapies. Thus, GRP78 expression may serve as a biomarker for tumor behavior and treatment response. Combination therapy suppressing GRP78 expression may represent a novel approach toward eradication of residual tumors. Furthermore, the recent discovery of GRP78 on the cell surface of cancer cells but not in normal tissues suggests that targeted therapy against cancer via surface GRP78 may be feasible.
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PMID:GRP78 induction in cancer: therapeutic and prognostic implications. 1744 54

We conducted a genetic yeast screen to identify Thermo-tolerance genes (TTOs) in maize kernel cDNA library. During the screening, we identified a maize clone (TTO6) that seemed to confer elevated heat tolerance in comparison to control cells. TTO6 cDNA (GenBank accession no. AY103785) encodes an 11-kDa protein which is 69% similarity to the Arabidopsis GASA4 gene. To further examine heat tolerance in Arabidopsis, we functionally characterized the GASA4 gene and found that heat induced GASA4 expression. Constitutive expression of GASA4 in Arabidopsis led to elevated heat tolerance in transgenic lines. Interestingly, endoplasmic reticulum chaperone expression analysis suggests that GASA4 influences BiP gene expression during heat stress.
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PMID:Enhanced tolerance to heat stress in transgenic plants expressing the GASA4 gene. 1776 29

Subtilase cytotoxin (SubAB) is the prototype of a recently discovered AB(5) cytotoxin family produced by certain strains of Shiga toxigenic Escherichia coli (STEC). The catalytic A subunit is a highly specific subtilase-like serine protease that cleaves the endoplasmic reticulum chaperone BiP. The toxin is lethal for mice, but the pathology it induces is poorly understood. Here, we show that intraperitoneal injection of SubAB causes microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment in mice--characteristics typical of Shiga toxin-induced hemolytic uremic syndrome. SubAB caused extensive microvascular thrombosis and other histologic damage in the brain, kidneys, and liver, as well as dramatic splenic atrophy. Peripheral blood leukocyte levels were increased at 24 h; there was also significant neutrophil infiltration in the liver, kidneys, and spleen and toxin-induced apoptosis at these sites. These findings raise the possibility that SubAB directly contributes to pathology in humans infected with strains of STEC that produce both Shiga toxin and SubAB.
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PMID:Pathologic changes in mice induced by subtilase cytotoxin, a potent new Escherichia coli AB5 toxin that targets the endoplasmic reticulum. 1776 34

A decisive step in the biosynthesis of many proteins is their partial or complete translocation across the eukaryotic endoplasmic reticulum membrane or the prokaryotic plasma membrane. Most of these proteins are translocated through a protein-conducting channel that is formed by a conserved, heterotrimeric membrane-protein complex, the Sec61 or SecY complex. Depending on channel binding partners, polypeptides are moved by different mechanisms: the polypeptide chain is transferred directly into the channel by the translating ribosome, a ratcheting mechanism is used by the endoplasmic reticulum chaperone BiP, and a pushing mechanism is used by the bacterial ATPase SecA. Structural, genetic and biochemical data show how the channel opens across the membrane, releases hydrophobic segments of membrane proteins laterally into lipid, and maintains the membrane barrier for small molecules.
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PMID:Protein translocation across the eukaryotic endoplasmic reticulum and bacterial plasma membranes. 1804 2

The endoplasmic reticulum chaperone and stress protein BiP has hitherto been considered as having only crucial intracellular cell protective functions. However, we have shown that BiP can be present in the extracellular environment and that it binds to a putative but as yet uncloned cell surface receptor. It will stimulate human monocytes via this receptor to express a gene profile that is anti-inflammatory. It will generate T cells with a regulatory function from human peripheral blood most likely by altering dendritic cell development. Intravenous BiP will both prevent and treat ongoing collagen induced arthritis in the DBA/1 mouse. Part of the suppression of arthritis is linked to interleukin (IL)4 as BiP-specific lymph node and spleen cells from these mice secrete IL4, and BiP has no suppressive effect on collagen induced arthritis in IL4 knockout mice. Lymph node and spleen cells isolated from mice administered intravenous BiP will suppress arthritis when transferred intravenously into recipient arthritic mice without any further BiP having to be given. Thus, both in vitro work with human peripheral blood mononuclear cells and in vivo work in the collagen arthritis model lead to the conclusion that BiP induces regulatory cells. Finally, intravenous BiP will ablate the inflammatory cell infiltrate and inflammatory cytokine expression in rheumatoid synovial membrane tissue transplanted subcutaneously into SCID mice. The conclusion from all this experimental work is that BiP may be a novel therapy for the treatment of patients with rheumatoid arthritis.
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PMID:BiP, an anti-inflammatory ER protein, is a potential new therapy for the treatment of rheumatoid arthritis. 1857 76


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