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 B cell antigen receptor (BCR) is comprised of four different polypeptides, immunoglobulin (Ig) heavy chain, Ig light chain, and the two signaling subunits of this receptor, Ig-alpha and Ig-beta. These four chains must assemble correctly in the endoplasmic reticulum (ER) before the BCR can be transported to the cell surface. The roles of the different chaperone proteins in mediating the assembly of mIg with the Ig-alpha/beta are not fully understood. To gain insights into the roles of chaperone proteins in BCR assembly, we have generated transfected non-lymphoid cell lines that express various intermediate assembled forms of the BCR and used them to examine the interactions of chaperone proteins with subunits of the BCR. We examined the interactions of BiP (GRP78), GRP94 and calnexin with the mu heavy chain, lambda light chain, Ig-alpha and Ig-beta. We report for the first time that Ig-alpha associates with GRP94 and that this interaction increases dramatically when other BCR chains are co-expressed. In contrast, the mu heavy chain interacts strongly with BiP (GRP78) when expressed by itself but this interaction is reduced when the lambda light chain is expressed, with the resulting mu(lambda) complexes interacting with GRP94 and calnexin. Thus, our data are consistent with the idea that there is an ordered association of BCR components with different protein chaperones during BCR assembly.
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PMID:Association of B lymphocyte antigen receptor polypeptides with multiple chaperone proteins. 1157 89

The heavy chain (HC) of the neonatal Fc receptor (FcRn) for IgG is non-convalently associated with beta(2)-microglobulin (beta(2)m). In beta(2)m(-/-) mice, FcRn functions are greatly impaired. We sought to determine how FcRn HC, particularly its structure and biogenesis, is affected by the absence of beta(2)m. Human FcRn HC, expressed from the beta(2)m-null cell line FO-1(FcRn), was present as a monomeric 45-kDa protein under reducing conditions but primarily as a 92-kDa oligomeric protein under non-reducing conditions. Two-dimensional electrophoresis and MS analysis showed that the 92-kDa protein was a dimer of the 45-kDa HC. Immunostaining showed that FcRn HC in FO-1(FcRn) was co-localized with the endoplasmic reticulum (ER) protein Bip/GRP78 but not with an endosome protein, EEA1. In contrast, FcRn HC in FO-1(FcRn+beta2m) was detected in both the ER and endosome. The dimeric HC in FcRn oligomers was free of beta(2)m association in FO-1(FcRn+beta2m). Mutation of non-paired cysteine residues at positions 48 and 251 within the human FcRn cDNA failed to eliminate the oligomers. The FcRn HC oligomers could be reduced by reconstitution of FO-1(FcRn) with beta(2)m or by balanced expression of FcRn HC with beta(2)m, or beta(2)m fused with a KDEL retention sequence. Similarly, the majority of FcRn HC isolated from neonatal beta(2)m(-/-) mice was in a dimeric form under non-reducing conditions. The amount of FcRn HC was significantly decreased in beta(2)m(-/-) mice and FO-1(FcRn). Furthermore, beta(2)m-free FcRn HC was sensitive to endoglycosidase digestion. These results indicate that FcRn HC alone can form disulphide-bonded oligomers in the ER, which may represent a misfolded protein. The beta(2)m association with FcRn HC is critical for correct folding of FcRn and exiting the ER for routing to endosomes and the cell surface.
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PMID:The heavy chain of neonatal Fc receptor for IgG is sequestered in endoplasmic reticulum by forming oligomers in the absence of beta2-microglobulin association. 1216 90

In this study, we demonstrate that the folding and assembly of IgG in transgenic tobacco plants is orchestrated by BiP (binding protein), an endoplasmic reticulum resident chaperone. Expression of BiP and calreticulin was examined in transgenic tobacco plants that express immunoglobulin chains, either singly or in combination to form IgG antibody. BiP mRNA expression was lowest in wild-type nontransformed plants and those that expressed immunoglobulin light chain alone. Higher mRNA levels were detected in plants expressing fully assembled immunoglobulin (light and heavy chains), and the most abundant levels of RNA transcript were found in those plants that expressed immunoglobulin heavy chain alone. Estimation of total BiP demonstrated a similar pattern, with the highest levels detected in plants expressing immunoglobulin heavy chain alone. Immunoprecipitation studies demonstrated that BiP was associated with immunoglobulin chains extracted from protoplast lysates, but not from secreted fluids. Again, most BiP was coprecipitated from plants expressing heavy chain only and those that produced full length IgG. The binding of BiP to Ig heavy chains was ATP-sensitive. Co-expression of heavy and light chain resulted in IgG assembly and displacement of BiP from the heavy chain as the amount of light chain increased. Although calreticulin mRNA and total protein levels varied in a similar manner to those of BiP in the transgenic plants, there was no evidence for association between calreticulin and Ig chains, by coimmunoprecipitation. The results indicate that BiP, but not calreticulin, takes part in immunoglobulin folding and assembly in transgenic plants.
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PMID:ER-resident chaperone interactions with recombinant antibodies in transgenic plants. 1247

The incidence of prostate diseases rises dramatically with age in men, yet little is understood of the mechanisms underlying prostatic senescence and its contribution to disease development in the gland. In Noble rats, aging of the ventral prostate (VP) is characterized morphologically by widespread atrophy of acini, increased accumulation of concretions in glandular lumen, infiltration of inflammatory cells, and focal epithelial atypia. We used a cDNA microarray containing 2388 known transcripts, together with the Tyramide Amplification System and t statistics, to identify differentially expressed genes in the VPs of young (3 months old) and old (16 months old) rats. A total of 78 VP genes were found to be differentially expressed by the two groups; in old rats, 65 VP genes (83%) showed reduced expression and 13 genes (17%) showed increased expression compared with young animals. The age-dependent underexpressed genes fell into several functional clusters: those involved in amino-acid metabolism, protein synthesis, protein secretion and degradation, vesicle/membrane trafficking, energy metabolism, signal transduction, spermidine and spermine syntheses, and cellular defense against stress. The overexpressed genes included iduronate 2-sulfatase, HLA class I locus C heavy chain, membrane cofactor protein of the complement system, TRPM-2, cadherin-associated protein-related, and X-CGD. Post hoc analyses confirmed a progressive decline in the expression of ribophorin II and BiP and a gradual increase in the expression of TRPM-2 in rat VPs as animals aged from 3 to 19 months old. In conclusion, the observed widespread declines in expression of genes involved in protein synthesis, protein fidelity maintenance, anabolism, growth inhibition, and energy metabolism, together with increased expression of genes implicated in cell survival in the VPs of senescent rats, may help explain the susceptibility of the prostates of elderly men to development of disease.
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PMID:Age-associated changes in histology and gene-expression profile in the rat ventral prostate. 1274 83

In this review we discuss the influence of chaperones on the general phenomena of folding as well as on the specific folding of an individual protein, MHC class I. MHC class I maturation is a highly sophisticated process in which the folding machinery of the endoplasmic reticulum (ER) is heavily involved. Understanding the MHC class I maturation per se is important since peptides loaded onto MHC class I molecules are the base for antigen presentation generating immune responses against virus, intracellular bacteria as well as tumours. This review discusses the early stages of MHC class I maturation regarding BiP and calnexin association, and differences in MHC class I heavy chain (HC) interaction with calnexin and calreticulin are highlighted. Late stage MHC class I maturation with focus on the dedicated chaperone tapasin is also discussed.
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PMID:Chaperones and folding of MHC class I molecules in the endoplasmic reticulum. 1278 24

Cholera toxin (CT) is transported from the cell surface to the endoplasmic reticulum (ER) from where it is translocated to the cytosol in a process depending on ATP and luminal ER proteins. To test whether the molecular chaperone BiP (heavy chain binding protein), which is an ER-luminal ATPase, was one of the required proteins the export of CT was analyzed using ER-derived CT-loaded microsomes. The resubstitution of extracted export-incompetent microsomes with purified BiP was sufficient to restore the export of CT. As BiP protected CT from aggregation it is proposed that BiP maintains CT in a soluble, export-competent state.
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PMID:BiP-dependent export of cholera toxin from endoplasmic reticulum-derived microsomes. 1462 8

We have employed an inverse engineering strategy based on quantitative proteome analysis to identify changes in intracellular protein abundance that correlate with increased specific recombinant monoclonal antibody production (qMab) by engineered murine myeloma (NS0) cells. Four homogeneous NS0 cell lines differing in qMab were isolated from a pool of primary transfectants. The proteome of each stably transfected cell line was analyzed at mid-exponential growth phase by two-dimensional gel electrophoresis (2D-PAGE) and individual protein spot volume data derived from digitized gel images were compared statistically. To identify changes in protein abundance associated with qMab datasets were screened for proteins that exhibited either a linear correlation with cell line qMab or a conserved change in abundance specific only to the cell line with highest qMab. Several proteins with altered abundance were identified by mass spectrometry. Proteins exhibiting a significant increase in abundance with increasing qMab included molecular chaperones known to interact directly with nascent immunoglobulins during their folding and assembly (e.g., BiP, endoplasmin, protein disulfide isomerase). 2D-PAGE analysis showed that in all cell lines Mab light chain was more abundant than heavy chain, indicating that this is a likely prerequisite for efficient Mab production. In summary, these data reveal both the adaptive responses and molecular mechanisms enabling mammalian cells in culture to achieve high-level recombinant monoclonal antibody production.
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PMID:Comparative proteomic analysis of GS-NS0 murine myeloma cell lines with varying recombinant monoclonal antibody production rate. 1545 12

We recently identified ERdj3 as a component of unassembled immunoglobulin (Ig) heavy chain:BiP complexes. ERdj3 also associates with a number of other protein substrates, including unfolded light chains, a nonsecreted Ig light chain mutant, and the VSV-G ts045 mutant at the nonpermissive temperature. We produced an ERdj3 mutant that was unable to stimulate BiP's ATPase activity in vitro or to bind BiP in vivo. This mutant retained the ability to interact with unfolded protein substrates, suggesting that ERdj3 binds directly to proteins instead of via interactions with BiP. BiP remained bound to unfolded light chains longer than ERdj3, which interacted with unfolded light chains initially, but quickly disassociated before protein folding was completed. This suggests that ERdj3 may bind first to substrates and serve to inhibit protein aggregation until BiP joins the complex, whereas BiP remains bound until folding is complete. Moreover, our findings support a model where interactions with BiP help trigger the release of ERdj3 from the substrate:BiP complex.
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PMID:ERdj3, a stress-inducible endoplasmic reticulum DnaJ homologue, serves as a cofactor for BiP's interactions with unfolded substrates. 1552 76

MTJ1/ERdj1 and its human homologue HTJ1 are membrane proteins that interact with the molecular chaperone BiP through their J-domain. HTJ1 also contains a C-terminal cytosolic region of unknown function that consists of two SANT domains separated by a spacer region. We recently showed that the second SANT domain of HTJ1 (SANT2) binds to alpha1-antichymotrypsin and alters its serpin activity [B. Kroczynska, C.M. Evangelista, S.S. Samant, E.C. Elguindi, S.Y. Blond, The SANT2 domain of the murine tumor cell DnaJ-like protein 1 human homologue interacts with alpha1-antichymotrypsin and kinetically interferes with its serpin inhibitory activity, J. Biol. Chem. 279 (2004) 11432-11443]. Here, we identified a new variant of human inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) that also interacts with the SANT2 domain of HTJ1. Biochemical, mutagenesis, and fluorescence studies demonstrate that SANT2 binds to a carboxyl-terminal fragment that corresponds to the last third of the new ITIH4 isoform sequence (residues 588-930). ITIH4 and MTJ1 co-immunoprecipitate from total liver protein extracts and SANT2 protects the ITIH4(588-930) recombinant fragment from being processed by kallikrein in vitro. This work reveals that the SANT2 domain of HTJ1 is a genuine protein-protein interaction module.
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PMID:BIP co-chaperone MTJ1/ERDJ1 interacts with inter-alpha-trypsin inhibitor heavy chain 4. 1627 2

Human cytomegalovirus (HCMV1) US11 and US2 proteins cause rapid degradation of major histocompatibility complex (MHC) molecules, apparently by ligating cellular endoplasmic reticulum (ER)-associated degradation machinery. Here, we show that US11 and US2 bind the ER chaperone BiP. Four related HCMV proteins, US3, US7, US9, and US10, which do not promote degradation of MHC proteins, did not bind BiP. Silencing BiP reduced US11- and US2-mediated degradation of MHC class I heavy chain (HC) without altering the synthesis or translocation of HC into the ER or the stability of HC in the absence of US11 or US2. Induction of the unfolded protein response (UPR) did not affect US11-mediated HC degradation and could not explain the stabilization of HC when BiP was silenced. Unlike in yeast, BiP did not act by maintaining substrates in a retrotranslocation-competent form. Our studies go beyond previous observations in mammalian cells correlating BiP release with degradation, demonstrating that BiP is functionally required for US2- and US11-mediated HC degradation. Further, US2 and US11 bound BiP even when HC was absent and degradation of US2 depended on HC. These data were consistent with a model in which US2 and US11 bridge HC onto BiP promoting interactions with other ER-associated degradation proteins.
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PMID:The role of BiP in endoplasmic reticulum-associated degradation of major histocompatibility complex class I heavy chain induced by cytomegalovirus proteins. 1673 24


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