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Protein folding in the ER

Manuel Bañó-Polo, Carlos Baeza-Delgado, Silvia Tamborero, Anthony Hazel, Brayan Grau, IngMarie Nilsson, Paul Whitley, James C Gumbart, Gunnar von Heijne, Ismael Mingarro
Integral membrane proteins are assembled into the ER membrane via a continuous ribosome-translocon channel. The hydrophobicity and thickness of the core of the membrane bilayer leads to the expectation that transmembrane (TM) segments minimize the cost of harbouring polar polypeptide backbones by adopting a regular pattern of hydrogen bonds to form α-helices before integration. Co-translational folding of nascent chains into an α-helical conformation in the ribosomal tunnel has been demonstrated previously, but the features governing this folding are not well understood...
December 7, 2018: Nature Communications
Ryan Thomas, Allison R Kermode
Small-molecule- enzyme enhancement therapeutics (EETs) have emerged as attractive agents for the treatment of lysosomal storage diseases (LSDs), a broad group of genetic diseases caused by mutations in genes encoding lysosomal enzymes, or proteins required for lysosomal function. The underlying enzyme deficiencies characterizing LSDs cause a block in the stepwise degradation of complex macromolecules (e.g. glycosaminoglycans, glycolipids and others), such that undegraded or partially degraded substrates progressively accumulate in lysosomal and non-lysosomal compartments, a process leading to multisystem pathology via primary and secondary mechanisms...
November 22, 2018: Molecular Genetics and Metabolism
Stephen Johnston, Shannon Puhalla, Duncan Wheatley, Alistair Ring, Peter Barry, Chris Holcombe, Jean Francois Boileau, Louise Provencher, André Robidoux, Mothaffar Rimawi, Stuart A McIntosh, Ibrahim Shalaby, Robert C Stein, Michael Thirlwell, David Dolling, James Morden, Claire Snowdon, Sophie Perry, Chester Cornman, Leona M Batten, Lisa K Jeffs, Andrew Dodson, Vera Martins, Arjun Modi, C Kent Osborne, Katherine L Pogue-Geile, Maggie Chon U Cheang, Norman Wolmark, Thomas B Julian, Kate Fisher, Mairead MacKenzie, Maggie Wilcox, Cynthia Huang Bartlett, Maria Koehler, Mitch Dowsett, Judith M Bliss, Samuel A Jacobs
PURPOSE: CDK4/6 inhibitors are used to treat estrogen receptor (ER)-positive metastatic breast cancer (BC) in combination with endocrine therapy. PALLET is a phase II randomized trial that evaluated the effects of combination palbociclib plus letrozole as neoadjuvant therapy. PATIENTS AND METHODS: Postmenopausal women with ER-positive primary BC and tumors greater than or equal to 2.0 cm were randomly assigned 3:2:2:2 to letrozole (2.5 mg/d) for 14 weeks (A); letrozole for 2 weeks, then palbociclib plus letrozole to 14 weeks (B); palbociclib for 2 weeks, then palbociclib plus letrozole to 14 weeks (C); or palbociclib plus letrozole for 14 weeks...
December 6, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Carine Beaupere, Vyacheslav M Labunskyy
During stress, accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers activation of the adaptive mechanisms that restore protein homeostasis. One mechanism that eukaryotic cells use to respond to ER stress is through activation of the unfolded protein response (UPR) signaling pathway, which initiates degradation of misfolded proteins and leads to inhibition of translation and increased expression of chaperones and oxidative folding components that enhance ER protein folding capacity. However, the mechanisms of adaptation to ER stress are not limited to the UPR...
December 3, 2018: Current Genetics
Ancy D Nalli, Lauren E Brown, Cheryl L Thomas, Thomas J Sayers, John A Porco, Curtis J Henrich
Rocaglamide has been reported to sensitize several cell types to TRAIL-induced apoptosis. In recent years, advances in synthetic techniques have led to generation of novel rocaglamide analogs. However, these have not been extensively analyzed as TRAIL sensitizers, particularly in TRAIL-resistant renal cell carcinoma cells. Evaluation of rocaglamide and analogs identified 29 compounds that are able to sensitize TRAIL-resistant ACHN cells to TRAIL-induced, caspase-dependent apoptosis with sub-µM potency which correlated with their potency as protein synthesis inhibitors and with loss of cFLIP protein in the same cells...
November 30, 2018: Scientific Reports
Zhenyu Wang, Liang Fang, Hui Shi, Zhao Yang
Endoplasmic reticulum (ER) stress acts as a protein folding and contributes to neuronal damage and neurological deterioration following intracerebral hemorrhage (ICH). Heat Shock Protein A5 (HSPA5) serves as an essential regulator of the endoplasmic reticulum (ER) stress response. However, the specific mechanism has not been will identified. Primary cortical neurons from C57BL/6 mice were subjected to erythrocyte lysates. Cell viability, microRNA and HSPA5 levels, and ER stress was detected. The interaction between microRNA and the target HSPA5 was identified by dual luciferase reporter gene assay...
November 29, 2018: Immunology Letters
Cathrine K Fog, Paola Zago, Erika Malini, Lukasz M Solanko, Paolo Peruzzo, Claus Bornaes, Raffaella Magnoni, Arnela Mehmedbasic, Nikolaj H T Petersen, Bruno Bembi, Johannes F M G Aerts, Andrea Dardis, Thomas Kirkegaard
BACKGROUND: Gaucher Disease is caused by mutations of the GBA gene which encodes the lysosomal enzyme acid beta-glucosidase (GCase). GBA mutations commonly affect GCase function by perturbing its protein homeostasis rather than its catalytic activity. Heat shock proteins are well known cytoprotective molecules with functions in protein homeostasis and lysosomal function and their manipulation has been suggested as a potential therapeutic strategy for GD. The investigational drug arimoclomol, which is in phase II/III clinical trials, is a well-characterized HSP amplifier and has been extensively clinically tested...
November 26, 2018: EBioMedicine
Inna Sabirzhanova, Clément Boinot, William B Guggino, Liudmila Cebotaru
BACKGROUND/AIMS: Cystic fibrosis (CF) is a lethal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR). ΔF508, the most common mutation, is a misfolded protein that is retained in the endoplasmic reticulum and degraded, precluding delivery to the cell surface [<xref ref-type="bibr" rid="ref1">1</xref>]. METHODS: Here we use a combination of western blotting, immunoprecipitation, and short circuit current techniques combined with confocal microscopy to address whether the SNARE attachment protein, STX8 plays a role in ΔF508's processing and movement out of the ER...
November 28, 2018: Cellular Physiology and Biochemistry
Tadashi Satoh, Koichi Kato
N-linked oligosaccharides attached to proteins act as tags for glycoprotein quality control, ensuring their appropriate folding and trafficking in cells. Interactions with a variety of intracellular lectins determine glycoprotein fates. Monoglucosylated glycoforms are the hallmarks of incompletely folded glycoproteins in the protein quality-control system, in which glucosidase II and UDP-glucose/glycoprotein glucosyltransferase are, respectively, responsible for glucose trimming and attachment. In this review, we summarize a recently emerging view of the structural basis of the functional mechanisms of these key enzymes as well as substrate N-linked oligosaccharides exhibiting flexible structures, as revealed by applying a series of biophysical techniques including small-angle X-ray scattering, X-ray crystallography, high-speed atomic force microscopy , electron microscopy , and computational simulation in conjunction with NMR spectroscopy...
2018: Advances in Experimental Medicine and Biology
Tatsuto Kiuchi, Masayuki Izumi, Yuki Mukogawa, Arisa Shimada, Ryo Okamoto, Akira Seko, Masafumi Sakono, Yoichi Takeda, Yukishige Ito, Yasuhiro Kajihara
The glycoprotein quality control (GQC) system in the endoplasmic reticulum (ER) effectively uses chaperone-type enzymes and lectins such as UDP-glucose:glycoprotein glucosyltransferase (UGGT), calnexin (CNX), calreticulin (CRT), protein di-sulfide bond isomerases (ERp57 or PDIs), and glucosidases to generate native-folded glycoproteins from nascent glycopoly-peptides. However, the individual processes of the GQC system at the molecular level are still unclear. We chemically syn-thesized a series of several homogeneous glycoproteins bearing M9-high-mannose type oligosaccharides (M9-glycan), such as erythropoietin (EPO), interferon- (IFN-), and interleukin 8 (IL8) and their misfolded counterparts, and used these glycopro-tein probes to better understand the GQC process...
November 26, 2018: Journal of the American Chemical Society
Vivek Kumar Pandey, Alpana Mathur, Poonam Kakkar
Endoplasmic reticulum (ER) is a crucial single membrane organelle that acts as a quality control system for cellular proteins as it is intricately involved in their synthesis, folding and trafficking to the respective targets. Type 2 diabetes is characterized by enhanced blood glucose level that promotes insulin resistance and hampers cellular glucose metabolism. Hyperglycemia provokes mitochondrial ROS production and glycation of proteins which exert a tremendous load on ER for conventional refolding of misfolded/unfolded and nascent proteins that perturb ER homeostasis resulting in apoptotic cell death...
November 21, 2018: Life Sciences
Zhe Zhang, Lu Zhang, Li Zhou, Yunlong Lei, Yuanyuan Zhang, Canhua Huang
Endoplasmic reticulum (ER) is a dynamic organelle orchestrating the folding and post-translational maturation of almost all membrane proteins and most secreted proteins. These proteins synthesized in the ER, need to form disulfide bridge to acquire specific three-dimensional structures for function. The formation of disulfide bridge is mediated via protein disulfide isomerase (PDI) family and other oxidoreductases, which contribute to reactive oxygen species (ROS) generation and consumption in the ER. Therefore, redox regulation of ER is delicate and sensitive to perturbation...
November 14, 2018: Redox Biology
Chloe L Rapp, Jing Li, Katherine E Badior, David B Williams, Joseph R Casey, Reinhart A F Reithmeier
The human solute carrier 26 (SLC26) gene family of anion transporters consists of 10 members (SLC26A1-A11, A10 being a pseudogene) that encode membrane glycoproteins with 14 transmembrane (TM) segments and a C-terminal cytoplasmic sulfate transporter anti-sigma antagonist (STAS) domain. Thus far, mutations in eight members of the SLC26 family (A1 - A6, A8 and A9) have been linked to diseases in humans. Our goal is to characterize the role of N-glycosylation and the effect of mutations in SLC26A2 and A3 proteins on their functional expression in transfected HEK-293 cells...
November 21, 2018: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
Antti Moilanen, Kati Korhonen, Mirva J Saaranen, Lloyd W Ruddock
Oxidative protein folding in the ER is driven mainly by oxidases of the endoplasmic reticulum oxidoreductin 1 (Ero1) family. Their action is regulated to avoid cell stress, including hyperoxidation. Previously published regulatory mechanisms are based on the rearrangement of active site and regulatory disulfides. In this study, we identify two novel regulatory mechanisms. First, both human Ero1 isoforms exist in a dynamic mixed disulfide complex with protein disulfide isomerase, which involves cysteines (Cys166 in Ero1α and Cys165 in Ero1β) that have previously been regarded as being nonfunctional...
June 2018: Life science alliance
Claus Brandt, Hendrik Nolte, Sinika Henschke, Linda Engström Ruud, Motoharu Awazawa, Donald A Morgan, Paula Gabel, Hans-Georg Sprenger, Martin E Hess, Stefan Günther, Thomas Langer, Kamal Rahmouni, Henning Fenselau, Marcus Krüger, Jens C Brüning
Adaptation of liver to the postprandial state requires coordinated regulation of protein synthesis and folding aligned with changes in lipid metabolism. Here we demonstrate that sensory food perception is sufficient to elicit early activation of hepatic mTOR signaling, Xbp1 splicing, increased expression of ER-stress genes, and phosphatidylcholine synthesis, which translate into a rapid morphological ER remodeling. These responses overlap with those activated during refeeding, where they are maintained and constantly increased upon nutrient supply...
November 15, 2018: Cell
Hisayo Jin, Mari Komita, Tomohiko Aoe
Background: Most neurodegenerative diseases are sporadic and develop with age. Degenerative neural tissues often contain intra- and extracellular protein aggregates, suggesting that the proteostasis network that combats protein misfolding could be dysfunctional in the setting of neurodegenerative disease. Binding immunoglobulin protein (BiP) is an endoplasmic reticulum (ER) chaperone that is crucial for protein folding and modulating the adaptive response in early secretory pathways. The interaction between BiP and unfolded proteins is mediated by the substrate-binding domain and nucleotide-binding domain with ATPase activity...
2018: Frontiers in Neuroscience
Ming Huang, Yinsheng Wang
Development of tamoxifen resistance remains a tremendous challenge for the treatment of estrogen-receptor (ER)-positive breast cancer. Small GTPases of the Ras superfamily play crucial roles in intracellular trafficking and cell signaling, and aberrant small-GTPase signaling is implicated in many types of cancer. In this study, we employed a targeted, quantitative proteomic approach that relies on stable-isotope labeling by amino acids in cell culture (SILAC), gel fractionation, and scheduled multiple-reaction-monitoring (MRM) analysis, to assess the differential expression of small GTPases in MCF-7 and the paired tamoxifen-resistant breast cancer cells...
November 30, 2018: Analytical Chemistry
Yunzhi Yang, Fengguang Ma, Zhengshuai Liu, Qian Su, Yuxiao Liu, Zhixue Liu, Yu Li
Autophagy is of key importance for eliminating aggregated proteins during the maintenance of cellular proteostasis in response to endoplasmic reticulum (ER) stress. However, the upstream signaling that mediates autophagy activation in response to ER stress is incompletely understood. In the study, in vivo and in vitro approaches were utilized, which include gain- and loss-of-function assays and mouse livers and human cell lines of tunicamycin-induced pharmacological ER stress. We report that calreticulin, a quality-control chaperone that binds to misfolded glycoproteins for refolding in the ER, is induced under ER stress...
November 14, 2018: Journal of Biological Chemistry
Kathleen A Trychta, Susanne Bäck, Mark J Henderson, Brandon K Harvey
Retention of critical endoplasmic reticulum (ER) luminal proteins needed to carry out diverse functions (e.g., protein synthesis and folding, lipid metabolism) is mediated through a carboxy-terminal ER retention sequence (ERS) and its interaction with KDEL receptors. Here, we demonstrate that depleting ER calcium causes mass departure of ERS-containing proteins from cells by overwhelming KDEL receptors. In addition, we provide evidence that KDELR2 and KDELR3, but not KDELR1, are unfolded protein response (UPR) genes upregulated as an adaptive response to counteract the loss of ERS-containing proteins, suggesting previously unknown isoform-specific functions of the KDEL receptors...
November 13, 2018: Cell Reports
Chao Qu, Jingyun Ma, Yejun Zhang, Chao Han, Liang Huang, Liming Shen, Hongyan Li, Xiaobo Wang, Jing Liu, Wei Zou
Glioblastoma (GBM) is a highly infiltrative and malignant primary brain tumor. Despite aggressive therapy, patients with GBM have a dismal prognosis with median survival of about one year. Tamoxifen (TAM), a selective estrogen receptor modulator (SERM), has been used to treat GBM for many years. ER-α36 is a novel variant of estrogen receptor-alpha66 (ER-α66) and can mediate cell proliferation through estrogen or anti-estrogen signaling in different cancer cells. Previously, we found that ER-α36 was highly expressed in GBM and was involved in the tamoxifen-sensitivity of glioblastoma cells...
November 11, 2018: Cancer Science
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