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Query: UNIPROT:P11021 (BiP)
 2,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sec71-1 and sec72-1 mutations were identified by a genetic assay that monitored membrane protein integration into the endoplasmic reticulum (ER) membrane of the yeast Saccharomyces cerevisiae. The mutations inhibited integration of various chimeric membrane proteins and translocation of a subset of water soluble proteins. In this paper we show that SEC71 encodes the 31.5-kDa transmembrane glycoprotein (p31.5) and SEC72 encodes the 23-kDa protein (p23) of the Sec63p-BiP complex. SEC71 is therefore identical to SEC66 (HSS1), which was previously shown to encode p31.5. DNA sequence analyses reveal that sec71-1 cells contain a nonsense mutation that removes approximately two-thirds of the cytoplasmic C-terminal domain of p31.5. The sec72-1 mutation shifts the reading frame of the gene encoding p23. Unexpectedly, the sec71-1 mutant lacks p31.5 and p23. Neither mutation is lethal, although sec71-1 cells exhibit a growth defect at 37 degrees C. These results show that p31.5 and p23 are important for the trafficking of a subset of proteins to the ER membrane.
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PMID:Nonlethal sec71-1 and sec72-1 mutations eliminate proteins associated with the Sec63p-BiP complex from S. cerevisiae. 784 22

Sindbis virus codes for two membrane glycoproteins, E1 and PE2, which assemble into heterodimers within the endoplasmic reticulum. We have examined the role of the molecular chaperone BiP (grp78) in the maturation of these two proteins. E1, which folds into its mature conformation via at least three intermediates differing in the configurations of their disulfide bonds, was found to interact strongly and transiently with BiP after synthesis. ATP depletion mediated by carbonyl cyanide m-chlorophenylhydrazone treatment results in the stabilization of complexes between BiP and E1. The depletion of intracellular ATP levels also greatly inhibits conversions between the E1 folding intermediates and results in the slow incorporation of E1 into disulfide-stabilized aggregates. These results suggest that the ATP-regulated binding and release of BiP have a role in modulating disulfide bond formation during E1 folding. In comparison with E1, very little PE2 is normally recovered in association with BiP. However, under conditions in which E1 folding is aberrant, increased amounts of PE2 become directly associated with BiP. The formation of these BiP-PE2 interactions occurs after E1 begins to misfold or fails to fold efficiently. We propose that nascent PE2 is stable prior to pairing with E1 for only a limited period of time, after which unpaired PE2 becomes recognized by BiP. This implies that the productive association of PE2 and E1 must occur within a restricted time frame and only after E1 has accomplished certain folding steps mediated by BiP binding and release. Kinetic studies which show that the pairing of E1 with PE2 is delayed after translocation support this conclusion.
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PMID:Involvement of the molecular chaperone BiP in maturation of Sindbis virus envelope glycoproteins. 785 97

In the absence of immunoglobulin heavy-chain expression, some immunoglobulin light (L) chains are retained and degraded within the cell. We investigated the fate of two different nonsecreted murine L chains which exhibit different half-lives (50 min and 3-4 hr). Our results demonstrate that both nonsecreted L chains are quantitatively bound to BiP as partially oxidized molecules. The kinetics of L-chain degradation coincided with those of L-chain dissociation from BiP, which suggests that these two processes are functionally related. L-chain degradation does not depend on vesicular transport, indicating that these soluble proteins are degraded in the endoplasmic reticulum (ER). In contrast, secreted L chains, which interact only transiently with BiP, are completely oxidized and are not degraded even when they are artificially retained in the ER. Our data support the model that, by means of BiP interaction, the ER degradation mechanism has the potential to discriminate between partially and completely folded molecules.
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PMID:Molecular chaperones involved in protein degradation in the endoplasmic reticulum: quantitative interaction of the heat shock cognate protein BiP with partially folded immunoglobulin light chains that are degraded in the endoplasmic reticulum. 787 56

The 94-kDa glucose-regulated protein (endoplasmin, grp94) is an abundant member of the 90-kDa molecular chaperone family in the endoplasmic reticulum. We have found earlier that the 50% homologous 90-kDa heat shock protein, hsp90, has ATP-binding site(s) and autophosphorylating activity (Csermely, P., and Kahn, C. R. (1991) J. Biol. Chem. 266, 4943-4950). In the present paper we demonstrate that highly purified grp94 is also able to autophosphorylate itself on serine and threonine residues. grp94 can be freed from the co-purifying casein kinase II by concanavalin A affinity chromatography, and its phosphorylation is unaffected by activators and inhibitors of numerous protein kinases known to associate with the homologous hsp90. The autophosphorylation persists in immunoprecipitates and in SDS-polyacrylamide gel-purified and renatured grp94. Autophosphorylation displays a monomolecular kinetics, is activated by micromolar calcium concentrations, has an extreme heat stability, and can utilize both ATP and GTP with relatively high km values of 243 +/- 14 microM and 116 +/- 23 microM, respectively. Sequence analysis of grp94 shows the presence of two ATP-binding sites. The major product of limited proteolysis of grp94 by chymotrypsin or papain is an N-terminal 85-kDa fragment that can bind to ATP-agarose but does not show autophosphorylation. Our data suggest that grp94 has an enzymatic function analogous in many respects to the similar activity of hsp70, hsp90, and grp78 (BiP). Autophosphorylation may participate in/regulate the complex formation of these proteins, so it may be involved in their chaperone function.
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PMID:Autophosphorylation of grp94 (endoplasmin). 789 Jul 76

Mammalian GRP78/BiP is a stress-inducible 78-kDa endoplasmic reticulum (ER) protein with molecular chaperone and calcium-binding properties. The transactivation of grp78 by the calcium ionophore A23187 provides a model system with which to study the signal transduction that allows mammalian cells to sense calcium depletion in intracellular stores and activate transcription of specific genes. Linker-scanning mutation analysis of the grp78 promoter reveals that the single most important regulatory element is C1, which contains a CCAAT motif most proximal to the TATA sequence. The C1 element is crucial for mediating the stimulatory effects by the upstream regulatory elements under normal and stress conditions. In this report, we establish that the heteromeric CCAAT-binding factor CBF is the major component of the C1-binding factor (C1F) in human cells. A GGAGG motif flanking the CCAAT sequence also contributes to high-affinity C1F/CBF binding. We show here that the binding of C1F in vitro is sensitive to the concentration of calcium ions. At high calcium ion concentrations, the C1F-binding activity is lower because of a higher dissociation rate. This binding characteristic correlates with the induction of grp78 transcription in response to the depletion of intracellular calcium stores. The strikingly similar behavior of C1F from nuclear extracts of control and A23187-treated cells further suggests that C1F itself does not undergo any major inherent changes after calium depletion stress. Rather, its binding property could be modulated by the immediate calcium ionic environment in stressed and nonstressed cells. On the basis of the in vitro and in vivo site occupancies of C1F and other stress-inducible changes of upstream regulatory complexes, we present a model to explain how C1F and other upstream factors can synergistically activate grp78 transcription in calcium-depleted cells.
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PMID:Transduction of calcium stress through interaction of the human transcription factor CBF with the proximal CCAAT regulatory element of the grp78/BiP promoter. 789 20

Starvation of mouse hepatoma cells for essential amino acids or glucose results in the ADP-ribosylation of the molecular chaperone BiP/GRP78. Addition of the missing nutrient to the medium reverses the reaction. The signal mediating the response to environmental nutrients involves the translational efficiency. An inhibitor of proteins synthesis, cycloheximide, or reduced temperature, both of which reduce translational efficiency, stimulate the ADP-ribosylation of BiP/GRP78. Inhibition of N-linked glycosylation of proteins results in the overproduction of BiP/GRP78. The over produced protein is not ADP-ribosylated suggesting that this is the functional form of BiP/GRP78. The over produced BiP/GRP78 can, however, be ADP-ribosylated if the cells are starved for an essential amino acid. BiP/GRP78 resides in the lumen of the endoplasmic reticulum where it participates in the assembly of secretory and integral membrane proteins. ADP-ribosylation of BiP/GRP78 during starvation is probably part of a nutritional stress response which conserves limited nutrients by slowing flow through the secretory pathway.
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PMID:ADP-ribosylation of the molecular chaperone GRP78/BiP. 789 57

Hsp47, an endoplasmic reticulum resident protein, has gelatin-binding and procollagen-binding properties and has been hypothesized to function as a molecular chaperone in regulating procollagen folding and/or assembly. In this report, we further investigate the interaction of Hsp47 with polysome-associated alpha 1(I) procollagen chains following antisense treatment of 3T6 cells. For these studies, we employed phosphorothioate oligodeoxynucleotides directed to the first five codons of Hsp47 that straddle the predicted translation initiation site of mouse Hsp47. Cells depleted of Hsp47 in this manner were observed to produce diminished amounts of fully elongated nascent alpha 1(I) procollagen while accumulating shorter procollagen peptides associated with peptidyl-tRNA. Pulse-labeling of cells with [35S]methionine followed by treatment with puromycin and immunoprecipitation with anti-Hsp47 and anti-procollagen antibodies revealed that Hsp47 is associated with alpha 1(I) procollagen at a very early point during translocation of the nascent procollagen chains. Although Hsp47 appears to possess properties similar to grp78/BiP, Hsp47 binding early during translocation favors a more specialized specific function relative to chain selection or completion of stable folding in type I procollagen.
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PMID:Hsp47 and the translation-translocation machinery cooperate in the production of alpha 1(I) chains of type I procollagen. 790 76

During their transit through the endoplasmic reticulum, newly synthesized light and heavy chains of immunoglobulins associate with two endoplasmic reticulum stress proteins. BiP/GRP78, a member of the HSP70 family, binds these polypeptides, presumably through promiscuously exposed hydrophobic sequences, soon after their translocation into the endoplasmic reticulum. GRP94, another endoplasmic reticulum stress protein homologous to HSP90, also associates with unassembled immunoglobulin chains, but its interaction is biochemically, kinetically and structurally distinct from BiP's. We report here that whereas BiP preferentially binds an early disulphide intermediate of light chain and dissociates within a few minutes, GRP94 exclusively binds fully oxidized molecules and dissociates with a half-time of 50 min. These results indicate that GRP94 is itself a chaperone which acts after BiP.
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PMID:Sequential interaction of the chaperones BiP and GRP94 with immunoglobulin chains in the endoplasmic reticulum. 791 87

Folding and assembly of polypeptides translocated into the rough endoplasmic reticulum (RER) is facilitated by a set of resident proteins in the lumen of the RER. We studied the regulation of synthesis of the RER luminal proteins immunoglobulin heavy chain binding protein (BiP) and protein disulfide isomerase (PDI), and of the cytosolic stress 70 protein (hsc70) after hormonal stimulation of the pancreatic exocrine secretory pathway. Their rate of synthesis was assessed at both mRNA and protein levels and under two experimental conditions that are associated with large increases in exocrine production. After in vivo stimulation of the pancreas by either endogenous release of cholecystokinin (CCK) following proteinase inhibitor feeding (FOY-305) or by in vivo infusion of the pancreatic secretagogue cerulein, the relative rates of synthesis detected for BiP and PDI were enhanced 2.5 to 4-fold compared to control. Interestingly, the kinetics and the degree of hsc70 mRNA induction were almost identical to those of BiP and PDI, suggesting coordinated hormonal regulation of BiP, PDI as hormonal stimulation was even twice that following heat shock treatment. The mRNA levels of calreticulin (CaBP3) increased up to 2.3-fold with a kinetic comparable to that of BiP, PDI and hsc 70, while CaBP1 and the RER membrane proteins, ribophorin I and the signal recognition particle receptor did not show any changes in their relative mRNA amounts after hormonal stimulation. The increase in the rates of PDI and chaperone biosynthesis exceeds the associated increase in total protein biosynthesis. In vitro experiments, using transformed rat acinar cells (AR4-2J) in which pancreatic enzyme synthesis can be induced by glycocorticoid hormones, demonstrated that induction of PDI and chaperone mRNA synthesis preceded extensive mRNA expression of secretory proteins.
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PMID:Hormonal regulation of protein disulfide isomerase and chaperone synthesis in the rat exocrine pancreas. 791 86

We have previously demonstrated that several endoplasmic reticulum (ER) proteins, including BiP, ERp72, grp94, and protein disulfide isomerase, bind to a denatured thyroglobulin (Tg) affinity column and can be specifically eluted by ATP (Nigam, S.K., Goldberg, A.L., Ho, S., Rohde, M.F., Bush, K.T., and Sherman, M.Y. (1994) J. Biol. Chem. 269, 1744-1749). Using chemical cross-linking, we now demonstrate that BiP, ERp72, and grp94 associate with Tg in two types of cultured thyroid cells, FRTL-5 and PCC13. Whereas BiP could be coimmunoprecipitated with anti-Tg antibodies in the absence of cross-linking, only trace amounts of ERp72 and grp94 were coimmunoprecipitated. Likewise, in both cell types, anti-BiP antibodies were able to coimmunoprecipitate Tg in the absence of cross-linking, though ERp72 and grp94 were only minimally present. Coprecipitation of BiP and Tg was abolished when ATP and Mg2+ were added to cell lysates. In contrast, after cross-linking, there was a large increase in the amount of ERp72 and grp94 that coimmunoprecipitated with anti-Tg antibodies, although there was only a slight increase in BiP. Similarly, in cross-linked lysates, grp94 and ERp72 were also coimmunoprecipitated with anti-BiP antibodies. An apparently novel 200-kDa protein was also consistently immunoprecipitated by anti-BiP antibodies in both cell types. In addition, anti-ERp72 antibodies coimmunoprecipitated Tg, BiP, and grp94 only after cross-linking. Analysis of uncross-linked and cross-linked samples by sucrose density gradient centrifugation confirmed that Tg, BiP, grp94, and ERp72 are present together in high molecular weight complexes only after treatment of cells with cross-linking reagent. These results suggest that ERp72, as well as BiP and grp94, function as molecular chaperones in the maturation of Tg, potentially as part of a macromolecular complex.
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PMID:Several endoplasmic reticulum stress proteins, including ERp72, interact with thyroglobulin during its maturation. 791 14


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