Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Intracellular distribution of selected reticuloplasmins, soluble proteins of the endoplasmic reticulum lumen, in rat mammary gland was investigated during pregnancy, lactation, and involution. During lactation the levels of the calcium binding protein calreticulin, and of protein disulfide isomerase, were elevated. Endoplasmic reticulum was as efficient as Golgi apparatus in sequestration and accumulation of Ca2+ from surrounding medium, as suggested from in vitro experiments with isolated cell fractions. Both protein disulfide isomerase and calreticulin were present in cytosol from homogenates of mammary gland prepared under mild conditions. Protein disulfide isomerase was abundant in intracellular lipid droplet precursors of milk lipid globules. Calreticulin and immunoglobulin binding protein (BiP, GRP 78) were associated with lipid droplets. Glucose-regulated protein (GRP 94) was not detected in association with intracellular lipid droplets. Milk lipid globule membrane lacked more than barely detectable quantities of protein disulfide isomerase, calreticulin, and immunoglobulin binding protein, suggesting that these proteins are lost from intracellular lipid droplets before or during their secretion as milk lipid globules. Immunocytochemical localization confirmed the presence of protein disulfide isomerase or calreticulin on intracellular lipid droplets and in non-endoplasmic reticulum regions of cells.
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PMID:Endoplasmic reticulum lumenal proteins of rat mammary gland. Potential involvement in lipid droplet assembly during lactation. 803 38

The major proteins in the lumen of the endoplasmic reticulum (ER) are thought to function in Ca2+ sequestration or as "molecular chaperones" in the folding and assembly of membrane or secreted proteins. Based on the ability of many chaperones to bind selectively to unfolded proteins and to dissociate from them upon ATP hydrolysis, we developed an affinity chromatography method to isolate proteins with these characteristics from pancreatic or liver ER. Seven ER proteins bound selectively to denatured protein columns and were specifically eluted by ATP (10(-6) M) but not by a nonhydrolyzable ATP analog. These proteins were identified with antibodies and microsequencing as the ER chaperone BiP (grp78), grp94, calreticulin, a novel 46-kDa protein that binds azido-ATP, as well as three members of the thioredoxin superfamily: protein-disulfide isomerase, ERp72, and a previously reported 50-kDa protein (p50). This set of seven proteins bound to and was eluted with ATP from a variety of denatured proteins, including histone, gelatin, alpha fetoprotein, thyroglobulin, lysozyme, casein, and IgG. The release of grp94, protein-disulfide isomerase, ERp72, calreticulin, and p50 was stimulated by Ca2+ in the presence of ATP. These proteins thus appear to function as Ca(2+)-dependent chaperones, which may account for the Ca2+ and ATP requirement for protein folding in the ER.
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PMID:A set of endoplasmic reticulum proteins possessing properties of molecular chaperones includes Ca(2+)-binding proteins and members of the thioredoxin superfamily. 829 23

We have produced single-chain antibody fragments (scFv) in Saccharomyces cerevisiae at levels up to 20 mg/L in shake flask culture by a combination of expression level tuning and overexpression of folding assistants. Overexpression of the chaperone BiP or protein disulfide isomerase (PDI) increases secretion titers 2-8 fold for five scFvs. The increases occur for scFv expression levels ranging from low copy to ER-saturating overexpression. The disulfide isomerase activity of PDI, rather than its chaperone activity, is responsible for the secretion increases. A synergistic increase in scFv production occurs upon cooverexpression of BiP and PDI.
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PMID:Increasing the secretory capacity of Saccharomyces cerevisiae for production of single-chain antibody fragments. 970 78

We compared the membrane proteins of autolysosomes isolated from leupeptin-administered rat liver with those of lysosomes. In addition to many polypeptides common to the two membranes, the autolysosomal membranes were found to be more enriched in endoplasmic reticulum lumenal proteins (protein-disulfide isomerase, calreticulin, ER60, BiP) and endosome/Golgi markers (cation-independent mannose 6-phosphate receptor, transferrin receptor, Golgi 58-kDa protein) than lysosomal membranes. The autolysosomal membrane proteins include three polypeptides (44, 35, and 32 kDa) whose amino-terminal sequences have not yet been reported. Combining immunoblotting and reverse transcriptase-polymerase chain reaction analyses, we identified the 44-kDa peptide as the intact subunit of betaine homocysteine methyltransferase and the 35- and 32-kDa peptides as two proteolytic fragments. Pronase digestion of autolysosomes revealed that the 44-kDa and 32-kDa peptides are present in the lumen, whereas the 35-kDa peptide is not. In primary hepatocyte cultures, the starvation-induced accumulation of the 32-kDa peptide occurs in the presence of E64d, showing that the 32-kDa peptide is formed from the sequestered 44-kDa peptide during autophagy. The accumulation is induced by rapamycin but completely inhibited by wortmannin, 3-methyladenine, and bafilomycin. Thus, detection of the 32-kDa peptide by immunoblotting can be used as a streamlined assay for monitoring autophagy.
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PMID:Autolysosomal membrane-associated betaine homocysteine methyltransferase. Limited degradation fragment of a sequestered cytosolic enzyme monitoring autophagy. 1032 31

Protein disulfide isomerase (PDI) interacts with secretory proteins, irrespective of their thiol content, late during translocation into the ER; thus, PDI may be part of the quality control machinery in the ER. We used yeast pdi1 mutants with deletions in the putative peptide binding region of the molecule to investigate its role in the recognition of misfolded secretory proteins in the ER and their export to the cytosol for degradation. Our pdi1 deletion mutants are deficient in the export of a misfolded cysteine-free secretory protein across the ER membrane to the cytosol for degradation, but ER-to-Golgi complex transport of properly folded secretory proteins is only marginally affected. We demonstrate by chemical cross-linking that PDI specifically interacts with the misfolded secretory protein and that mutant forms of PDI have a lower affinity for this protein. In the ER of the pdi1 mutants, a higher proportion of the misfolded secretory protein remains associated with BiP, and in export-deficient sec61 mutants, the misfolded secretory protein remain bounds to PDI. We conclude that the chaperone PDI is part of the quality control machinery in the ER that recognizes terminally misfolded secretory proteins and targets them to the export channel in the ER membrane.
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PMID:Export of a cysteine-free misfolded secretory protein from the endoplasmic reticulum for degradation requires interaction with protein disulfide isomerase. 1061 3

The maturation of lipoprotein lipase (LPL) into a catalytically active enzyme was believed to occur only after its transport from the endoplasmic reticulum (ER) to the Golgi apparatus. To test this hypothesis, LPL located in these two subcellular compartments was separated and compared. Heparin affinity chromatography resolved low affinity, inactive LPL displaying ER characteristics from a high affinity, active fraction exhibiting both ER and Golgi forms. The latter forms were further separated by beta-ricin chromatography and were found to have comparable activities per unit of LPL mass. Thus, LPL must reach a functional conformation in the ER. Active LPL, regardless of its cellular location, exhibited the expected dimer conformation. However, inactive LPL, found only in the ER, was highly aggregated. Kinetic analysis indicated a concurrent formation of LPL dimer and aggregate and indicated that the two forms have dissimilar fates. Whereas the dimer remained stable even when confined to the ER, the aggregate was degraded. Degradation rates were not affected by proteasomal or lysosomal inhibitors but were markedly reduced by ATP depletion. Lowering the redox potential in the ER by dithiothreitol caused the dimer to associate with calnexin, BiP, and protein-disulfide isomerase to form large, inactive complexes; dithiothreitol removal induced complex dissociation with restoration of the functional LPL dimer. In contrast, the LPL aggregate was only poorly associated with ER chaperones, appearing to be trapped in an irreversible, inactive conformation destined for ER degradation.
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PMID:Maturation of lipoprotein lipase in the endoplasmic reticulum. Concurrent formation of functional dimers and inactive aggregates. 3142 May 23

A complex array of chaperones and enzymes reside in the endoplasmic reticulum (ER) to assist the folding and assembly of and the disulfide bond formation in nascent secretory proteins. Here we characterize a novel human putative ER co-chaperone (ERdj5) containing domains resembling DnaJ, protein-disulfide isomerase, and thioredoxin domains. Homologs of ERdj5 have been found in Caenorhabditis elegans and Mus musculus. In vitro experiments demonstrated that ERdj5 interacts via its DnaJ domain with BiP in an ATP-dependent manner. ERdj5 is a ubiquitous protein localized in the ER and is particularly abundant in secretory cells. Its transcription is induced during ER stress, suggesting potential roles for ERdj5 in protein folding and translocation across the ER membrane.
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PMID:ERdj5, an endoplasmic reticulum (ER)-resident protein containing DnaJ and thioredoxin domains, is expressed in secretory cells or following ER stress. 1241 43

In the present study, total proteins from a tissue of an infiltrating ductal carcinoma of the breast (IDCA) were compared by the two-dimensional electrophoresis (2D-PAGE) to proteins from an adjacent non-neoplastic breast tissue. Analysis of multiple gels for each sample identified nine proteins present in the tumor sample that were less present in the matched normal adjacent breast tissue and four proteins present at higher levels in the normal tissue. The altered proteins were identified by matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry and search in protein databases. Protein disulfide isomerase, BiP protein, calreticulin, cathepsin D, inorganic pyrophosphatase, vimentin, apolipoprotein A1 precursor, tropomyosin 4 and beta5-tubulin were identified as being significantly over-expressed in the IDCA with regard to the normal tissue. The expression of fibrinogen E-fragment (known as anti-angiogenic factor) as well as of fibrin E, Pro2619 and actinG1 was found to be inhibited in the tumor sample. The identified proteins might play an important role during malignant transformation, breast cancer progression, and angiogenesis as well as in cellular signaling. This study demonstrates quantitative and qualitative changes in protein abundance between IDCA and normal tissue. The identification of these differentially expressed proteins could lead to a better understanding of the molecular events linked to breast cancer progression.
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PMID:Expression of fibrinogen E-fragment and fibrin E-fragment is inhibited in the human infiltrating ductal carcinoma of the breast: the two-dimensional electrophoresis and MALDI-TOF-mass spectrometry analyses. 1621 Dec 39

The pro-oxidant effect of L-ascorbic acid (LAA) is toxic to leukemia cells. LAA induces the oxidation of glutathione to its oxidized form (GSSG) and this is followed by a concentration-dependent H(2)O(2) accumulation, which occurs in parallel to the induction of apoptosis. To identify early protein targets of LAA in leukemia cells, we used a differential proteomics approach in NB4 human leukemia cells treated with 0.5 mM of LAA for 30 min. This exposure was determined to efficiently block cellular proliferation and to activate oxidative stress-inducible apoptosis. We identified nine proteins that sensitively reacted to LAA treatment by using two-dimensional (2-D) gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight-MS. A subunit of protein-disulfide isomerase (a thiol/disulfide exchange catalyst) and immunoglobulin-heavy-chain binding protein (BiP, identical to Hsp70 chaperone) showed quantitative expression profile differences. A myeloid leukemia associated antigen protein (a tropomyosin isoform) showed changes in pI as a result of phosphorylation. Our studies demonstrate for the first time that the addition of LAA to cells results in an immediate change in the intracellular thiol/disulfide condition and that this includes an increase in the GSH oxidation with changes in the superfamily of thiol/disulfide exchange catalysts. These results suggest that LAA oxidizes intracellular reduced glutathione and modulates disulfide bond formation in proteins.
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PMID:A proteomic approach to the identification of early molecular targets changed by L-ascorbic acid in NB4 human leukemia cells. 1692 50

The production of erythrocytes requires the massive synthesis of red cell-specific proteins including hemoglobin, cytoskeletal proteins, as well as membrane glycoproteins glycophorin A (GPA) and anion exchanger 1 (AE1). We found that during the terminal differentiation of human CD34(+) erythroid progenitor cells in culture, key components of the endoplasmic reticulum (ER) protein translocation (Sec61alpha), glycosylation (OST48), and protein folding machinery, chaperones BiP, calreticulin (CRT), and Hsp90 were maintained to allow efficient red cell glycoprotein biosynthesis. Unexpected was the loss of calnexin (CNX), an ER glycoprotein chaperone, and ERp57, a protein-disulfide isomerase, as well as a major decrease of the cytosolic chaperones, Hsc70 and Hsp70, components normally involved in membrane glycoprotein folding and quality control. AE1 can traffic to the cell surface in mouse embryonic fibroblasts completely deficient in CNX or CRT, whereas disruption of the CNX/CRT-glycoprotein interactions in human K562 cells using castanospermine did not affect the cell-surface levels of endogenous GPA or expressed AE1. These results demonstrate that CNX and ERp57 are not required for major glycoprotein biosynthesis during red cell development, in contrast to their role in glycoprotein folding and quality control in other cells.
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PMID:Loss of specific chaperones involved in membrane glycoprotein biosynthesis during the maturation of human erythroid progenitor cells. 1925 25


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