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

We identified a mammalian BiP-associated protein, BAP, using a yeast two-hybrid screen that shared low homology with yeast Sls1p/Sil1p and mammalian HspBP1, both of which regulate the ATPase activity of their Hsp70 partner. BAP encoded an approximately 54-kDa protein with an N-terminal endoplasmic reticulum (ER) targeting sequence, two sites of N-linked glycosylation, and a C-terminal ER retention sequence. Immunofluorescence staining demonstrated that BAP co-localized with GRP94 in the endoplasmic reticulum. BAP was ubiquitously expressed but showed the highest levels of expression in secretory organ tissues, a pattern similar to that observed with BiP. BAP binding was affected by the conformation of the ATPase domain of BiP based on in vivo binding studies with BiP mutants. BAP stimulated the ATPase activity of BiP when added alone or together with the ER DnaJ protein, ERdj4, by promoting the release of ADP from BiP. Together, these data demonstrate that BAP serves as a nucleotide exchange factor for BiP and provide insights into the mechanisms that control protein folding in the mammalian ER.
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PMID:BAP, a mammalian BiP-associated protein, is a nucleotide exchange factor that regulates the ATPase activity of BiP. 1235 56

Mono-ADP-ribosylation is the enzymatic transfer of ADP-ribose from NAD(+) to acceptor proteins. It is catalysed by cellular ADP-ribosyltransferases and certain bacterial toxins. There are two subclasses of cellular enzymes: the ectoenzymes that modify targets such as integrins, defensin and other cell surface molecules; and the intracellular enzymes that act on proteins involved in cell signalling and metabolism, such as the beta-subunit of heterotrimeric G proteins, GRP78/BiP and elongation factor 2. The genes that encode the ectoenzymes have been cloned and their protein products are well characterized, yet little is known about the intracellular ADP-ribosyltransferases, which may be part of a novel protein family with an important role in regulating cell function. ADP-ribosylation usually leads to protein inactivation, providing a mechanism to inhibit protein functions in both physiological and pathological conditions.
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PMID:Functional aspects of protein mono-ADP-ribosylation. 1272 63

The Sec61 translocon of the endoplasmic reticulum membrane forms an aqueous pore that is gated by the lumenal Hsp70 chaperone BiP. We have explored the molecular mechanisms governing BiP-mediated gating activity, including the coupling between gating and the BiP ATPase cycle, and the involvement of the substrate-binding and J domain-binding regions of BiP. Translocon gating was assayed by measuring the collisional quenching of fluorescent probes incorporated into nascent chains of translocation intermediates engaged with microsomes containing various BiP mutants and BiP substrate. Our results indicate that BiP must assume the ADP-bound conformation to seal the translocon, and that the reopening of the pore requires an ATP binding-induced conformational change. Further, pore closure requires functional interactions between both the substrate-binding region and the J domain-binding region of BiP and membrane proteins. The mechanism by which BiP mediates translocon pore closure and opening is therefore similar to that in which Hsp70 chaperones associate with and dissociate from substrates.
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PMID:The molecular mechanisms underlying BiP-mediated gating of the Sec61 translocon of the endoplasmic reticulum. 1568 29

The mono(ADP-ribosyl)ation reaction is a post-translational modification that is catalysed by both bacterial toxins and eukaryotic enzymes, and that results in the transfer of ADP-ribose from betaNAD+ to various acceptor proteins. In mammals, both intracellular and extracellular reactions have been described; the latter are due to glycosylphosphatidylinositol-anchored or secreted enzymes that are able to modify their targets, which include the purinergic receptor P2X7, the defensins and the integrins. Intracellular mono(ADP-ribosyl)ation modifies proteins that have roles in cell signalling and metabolism, such as the chaperone GRP78/BiP, the beta-subunit of heterotrimeric G-proteins and glutamate dehydrogenase. The molecular identification of the intracellular enzymes, however, is still missing. A better molecular understanding of this reaction will help in the full definition of its role in cell physiology and pathology.
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PMID:Physiological relevance of the endogenous mono(ADP-ribosyl)ation of cellular proteins. 1615 79

ER-60 is a PDI family protein that has protein thiol-disulfide oxidoreductase activity. It has been shown to associate with BiP in the endoplasmic reticulum. Here, we analyzed the cooperation of ER-60 and BiP in the oxidative refolding of denatured proteins in vitro. ER-60 facilitated the refolding of 20 or 30% of denatured alpha-lactalbumin or ribonuclease B during incubation for 80 min, and these levels of nearly doubled on the addition of BiP to the reaction mixture. BiP alone could not refold denatured ribonuclease B, but could refold denatured alpha-lactalbumin a little. Enhancement of oxidative refolding of alpha-lactalbumin by ER-60 could be detected only when ER-60 was present from the start of refolding. On surface plasmon resonance analysis, ER-60 was shown to associate with BiP. The association was not influenced by ATP or ADP. Domains a and/or b' of ER-60 were implicated in the association with BiP.
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PMID:Cooperation of ER-60 and BiP in the oxidative refolding of denatured proteins in vitro. 1642 6

The endoplasmic reticulum HSP70 chaperone BiP/Kar2p is both the sensor for the unfolded protein response (UPR) in the yeast Saccharomyces cerevisiae and a target of transcriptional up-regulation by this signaling pathway. In this study, the molecular form of Kar2p that interacts with the Ire1p transmembrane receptor kinase to inhibit UPR signaling was shown to be the substrate-free, ATP-bound conformation. Oligosaccharide shielding experiments localized the binding site for Ire1p to the top of the back face of lobe IB of the Kar2p ATPase domain. The interaction between Kar2p and Ire1p is abolished by substitution of glutamic acid for glutamine 88, a residue on the surface of lobe IB that is likely to be shielded by ectopic oligosaccharide side-chains that also prevented the interaction between the two proteins. Glutamine 88 is conserved significantly throughout the HSP70 chaperone family and others have shown that the NMR resonances of the corresponding glutamine residue in Thermus thermophilus DnaK display chemical shift perturbations between the ATP-bound and ADP-bound states and in the presence of a substrate peptide. We conclude that glutamine 88 is part of or close to the Ire1p-binding site displayed on the ATP-bound conformation of Kar2p. Binding of an unfolded polypeptide to the substrate-binding domain of Kar2p could alter the positioning of glutamine 88 and other residues on lobe IB involved in binding Ire1p, releasing Ire1p for activation of UPR signaling.
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PMID:Lobe IB of the ATPase domain of Kar2p/BiP interacts with Ire1p to negatively regulate the unfolded protein response in Saccharomyces cerevisiae. 1727 61

Many metabolic reactions in the endoplasmic reticulum (ER) require high levels of energy in the form of ATP, which is important for cell viability. Here, we report on an adenine nucleotide transporter residing in the ER membranes of Arabidopsis thaliana (ER-ANT1). Functional integration of ER-ANT1 in the cytoplasmic membrane of intact Escherichia coli cells reveals a high specificity for an ATP/ADP antiport. Immunodetection in transgenic ER-ANT1-C-MYC-tag Arabidopsis plants and immunogold labeling of wild-type pollen grain tissue using a peptide-specific antiserum reveal the localization of this carrier in ER membranes. Transgenic ER-ANT1-promoter-beta-glucuronidase Arabidopsis lines show high expression in ER-active tissues (i.e., pollen, seeds, root tips, apical meristems, or vascular bundles). Two independent ER-ANT1 Arabidopsis knockout lines indicate a high physiological relevance of ER-ANT1 for ATP transport into the plant ER (e.g., disruption of ER-ANT1 results in a drastic retardation of plant growth and impaired root and seed development). In these ER-ANT1 knockout lines, the expression levels of several genes encoding ER proteins that are dependent on a sufficient ATP supply (i.e., BiP [for luminal binding protein] chaperones, calreticulin chaperones, Ca2+-dependent protein kinase, and SEC61) are substantially decreased.
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PMID:Identification of a novel adenine nucleotide transporter in the endoplasmic reticulum of Arabidopsis. 1829 23

Following endoplasmic reticulum (ER) stress, eukaryotic cells trigger a conserved signal transduction pathway called the unfolded protein response (UPR) that regulates the ER's capacity to perform protein folding according to cellular demand. In Saccharomyces cerevisiae, the UPR is initiated by Ire1, a type I transmembrane serine/threonine kinase/endoribonuclease, that senses unfolded protein levels within the ER in collaboration with the ER Hsp70-family member, BiP/Kar2. Here, we report on the characterization of the Yarrowia lipolytica Ire1 ortholog. Our results show that Sls1, a nucleotide exchange factor for BiP, has important functions in regulating ER stress and the interaction of BiP and Ire1. They suggest that Sls1 regulates this interaction, by stimulating the conversion of BiP from the ADP-bound to the ATP-bound state, which favors its interaction with Ire1. Moreover, we identified known and new partners for Ire1 using the Tandem Affinity Purification (TAP) approach.
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PMID:Characterization of Ire1 in the yeast Yarrowia lipolytica reveals an important role for the Sls1 nucleotide exchange factor in unfolded protein response regulation. 1842 59

ER stress is activated in a number of important diseases such as diabetes, cancer, and neurodegeneration, but the molecular interactions governing the response are still being elucidated. In the absence of stress, protein complexes exist between the ER-resident chaperone BiP and three transmembrane signalling molecules which are responsible for signal transmission. Previous results suggested that cofactors might participate in these interactions, but the molecular details are not well understood. We coexpressed BiP and the lumenal domains of each of the three ER stress transducers and copurified the complexes in the presence of ATP and ADP in order to better understand how the complex is formed. ATP, but not ADP, was required to isolate the BiP-IRE1 and the BiP-PERK complexes, but the BiP-ATF6 complex was purified in all conditions tested. Based on the results, we hypothesize that in contrast to its mode of binding ATF6 and unfolded proteins, BiP binds to IRE1 and PERK in a different manner.
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PMID:Binding of human BiP to the ER stress transducers IRE1 and PERK requires ATP. 2244 26

BiP is the predominant DnaK/Hsp70-type chaperone protein in the ER. It is required for folding and assembling newly synthesized ER client proteins, yet having too much BiP inhibits folding. In this issue, Chambers et al. (2012. J. Cell Biol. doi:10.1083/jcb.201202005) report that ADP ribosylation of BiP provides a reversible switch that fine tunes BiP activity according to need.
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PMID:A first line of defense against ER stress. 2286 98


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