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Unfolded Proteins

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https://www.readbyqxmd.com/read/28931068/erk1-2-signalling-protects-against-apoptosis-following-endoplasmic-reticulum-stress-but-cannot-provide-long-term-protection-against-bax-bak-independent-cell-death
#1
Nicola J Darling, Kathryn Balmanno, Simon J Cook
Disruption of protein folding in the endoplasmic reticulum (ER) causes ER stress. Activation of the unfolded protein response (UPR) acts to restore protein homeostasis or, if ER stress is severe or persistent, drive apoptosis, which is thought to proceed through the cell intrinsic, mitochondrial pathway. Indeed, cells that lack the key executioner proteins BAX and BAK are protected from ER stress-induced apoptosis. Here we show that chronic ER stress causes the progressive inhibition of the extracellular signal-regulated kinase (ERK1/2) signalling pathway...
2017: PloS One
https://www.readbyqxmd.com/read/28929194/adapting-secretory-proteostasis-and-function-through-the-unfolded-protein-response
#2
Madeline Y Wong, Andrew S DiChiara, Patreece H Suen, Kenny Chen, Ngoc-Duc Doan, Matthew D Shoulders
Cells address challenges to protein folding in the secretory pathway by engaging endoplasmic reticulum (ER)-localized protective mechanisms that are collectively termed the unfolded protein response (UPR). By the action of the transmembrane signal transducers IRE1, PERK, and ATF6, the UPR induces networks of genes whose products alleviate the burden of protein misfolding. The UPR also plays instructive roles in cell differentiation and development, aids in the response to pathogens, and coordinates the output of professional secretory cells...
September 20, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28929175/tusc3-functional-duality-of-a-cancer-gene
#3
REVIEW
Kateřina Vašíčková, Peter Horak, Petr Vaňhara
Two decades ago, following a systematic screening of LOH regions on chromosome 8p22, TUSC3 has been identified as a candidate tumor suppressor gene in ovarian, prostate and pancreatic cancers. Since then, a growing body of evidence documented its clinical importance in various other types of cancers, and first initial insights into its molecular function and phenotypic effects have been gained, though the precise role of TUSC3 in different cancers remains unclear. As a part of the oligosaccharyltransferase complex, TUSC3 localizes to the endoplasmic reticulum and functions in final steps of N-glycosylation of proteins, while its loss evokes the unfolded protein response...
September 19, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28928480/bisoprolol-protects-myocardium-cells-against-ischemia-reperfusion-injury-by-attenuating-unfolded-protein-response-in-rats
#4
Chengcheng Zhang, Songqing He, Yanming Li, Feng Li, Zhengbing Liu, Jing Liu, Jianbin Gong
Bisoprolol (B) exerts potential cardioprotective effects against myocardial ischemia/reperfusion (I/R) injury. Unfolded protein response (UPR) attenuates I/R injury induced apoptosis by reducing oxidative damage and inflammation response. The current study investigated whether the protective effects of bisoprolol resulted from modulating UPR and anti-inflammatory during myocardial I/R condition and elucidated its potential mechanisms. Sprague-Dawley rats were treated with B in the absence or presence of the injected UPR activator dithiothreitol (DTT) and then subjected to myocardial I/R surgery...
September 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28928140/selenoprotein-t-is-a-novel-ost-subunit-that-regulates-upr-signaling-and-hormone-secretion
#5
Abdallah Hamieh, Dorthe Cartier, Houssni Abid, André Calas, Carole Burel, Christine Bucharles, Cedric Jehan, Luca Grumolato, Marc Landry, Patrice Lerouge, Youssef Anouar, Isabelle Lihrmann
Selenoprotein T (SelT) is a recently characterized thioredoxin-like protein whose expression is very high during development, but is confined to endocrine tissues in adulthood where its function is unknown. We report here that SelT is required for adaptation to the stressful conditions of high hormone level production in endocrine cells. Using immunofluorescence and TEM immunogold approaches, we find that SelT is expressed at the endoplasmic reticulum membrane in all hormone-producing pituitary cell types. SelT knockdown in corticotrope cells promotes unfolded protein response (UPR) and ER stress and lowers endoplasmic reticulum-associated protein degradation (ERAD) and hormone production...
September 19, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28926611/activation-of-the-unfolded-protein-response-in-sarcoma-cells-treated-with-rapamycin-or-temsirolimus
#6
Joseph W Briggs, Ling Ren, Kristi R Chakrabarti, Yien Che Tsai, Allan M Weissman, Ryan J Hansen, Daniel L Gustafson, Yousuf A Khan, Jonathan D Dinman, Chand Khanna
Activation of the unfolded protein response (UPR) in eukaryotic cells represents an evolutionarily conserved response to physiological stress. Here, we report that the mTOR inhibitors rapamycin (sirolimus) and structurally related temsirolimus are capable of inducing UPR in sarcoma cells. However, this effect appears to be distinct from the classical role for these drugs as mTOR inhibitors. Instead, we detected these compounds to be associated with ribosomes isolated from treated cells. Specifically, temsirolimus treatment resulted in protection from chemical modification of several rRNA residues previously shown to bind rapamycin in prokaryotic cells...
2017: PloS One
https://www.readbyqxmd.com/read/28926061/network-based-modelling-and-percolation-analysis-of-conformational-dynamics-and-activation-in-the-cdk2-and-cdk4-proteins-dynamic-and-energetic-polarization-of-the-kinase-lobes-may-determine-divergence-of-the-regulatory-mechanisms
#7
G M Verkhivker
The overarching goal of delineating molecular principles underlying differentiation of the activation mechanisms in cyclin-dependent kinases (CDKs) is important for understanding regulatory divergences among closely related kinases which can be exploited in drug discovery of targeted and allosteric inhibitors. To systematically characterize dynamic, energetic and network signatures of the activation mechanisms, we combined atomistic simulations and elastic network modeling with the analysis of the residue interaction networks and rigidity decomposition of the CDK2-cyclin A and CDK4-cyclin D1/D3 complexes...
September 19, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28925976/shiga-toxin-therapeutics-beyond-neutralization
#8
REVIEW
Gregory Hall, Shinichiro Kurosawa, Deborah J Stearns-Kurosawa
Ribotoxic Shiga toxins are the primary cause of hemolytic uremic syndrome (HUS) in patients infected with Shiga toxin-producing enterohemorrhagic Escherichia coli (STEC), a pathogen class responsible for epidemic outbreaks of gastrointestinal disease around the globe. HUS is a leading cause of pediatric renal failure in otherwise healthy children, resulting in a mortality rate of 10% and a chronic morbidity rate near 25%. There are currently no available therapeutics to prevent or treat HUS in STEC patients despite decades of work elucidating the mechanisms of Shiga toxicity in sensitive cells...
September 19, 2017: Toxins
https://www.readbyqxmd.com/read/28924219/mesoscopic-model-for-dna-g-quadruplex-unfolding
#9
A E Bergues-Pupo, I Gutiérrez, J R Arias-Gonzalez, F Falo, A Fiasconaro
Genomes contain rare guanine-rich sequences capable of assembling into four-stranded helical structures, termed G-quadruplexes, with potential roles in gene regulation and chromosome stability. Their mechanical unfolding has only been reported to date by all-atom simulations, which cannot dissect the major physical interactions responsible for their cohesion. Here, we propose a mesoscopic model to describe both the mechanical and thermal stability of DNA G-quadruplexes, where each nucleotide of the structure, as well as each central cation located at the inner channel, is mapped onto a single bead...
September 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28924169/the-clpxp-protease-is-dispensable-for-degradation-of-unfolded-proteins-in-staphylococcus-aureus
#10
Steen G Stahlhut, Abdulelah A Alqarzaee, Camilla Jensen, Niclas S Fisker, Ana R Pereira, Mariana G Pinho, Vinai Chittezham Thomas, Dorte Frees
In living cells intracellular proteolysis is crucial for protein homeostasis, and ClpP proteases are conserved between eubacteria and the organelles of eukaryotic cells. In Staphylococcus aureus, ClpP associates to the substrate specificity factors, ClpX and ClpC forming two ClpP proteases, ClpXP and ClpCP. To address how individual ClpP proteases impact cell physiology, we constructed a S. aureus mutant expressing ClpX with an I265E substitution in the ClpP recognition tripeptide of ClpX. This mutant cannot degrade established ClpXP substrates confirming that the introduced amino acid substitution abolishes ClpXP activity...
September 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28924165/manf-regulates-hypothalamic-control-of-food-intake-and-body-weight
#11
Su Yang, Huiming Yang, Renbao Chang, Peng Yin, Yang Yang, Weili Yang, Shanshan Huang, Marta A Gaertig, Shihua Li, Xiao-Jiang Li
The hypothalamus has a vital role in controlling food intake and energy homeostasis; its activity is modulated by neuropeptides and endocrine factors. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic factor that is also localized in the endoplasmic reticulum (ER) in neurons. Here we show that MANF is highly enriched in distinct nuclei of the mouse hypothalamus, and that MANF expression in the hypothalamus is upregulated in response to fasting. Increasing or decreasing hypothalamic MANF protein levels causes hyperphagia or hypophagia, respectively...
September 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28923469/thermodynamics-and-kinetics-of-single-chain-monellin-folding-with-structural-insights-into-specific-collapse-in-the-denatured-state-ensemble
#12
Hiranmay Maity, Govardhan Reddy
Proteins, which behave as random coils in high denaturant concentrations undergo collapse transition similar to polymers on denaturant dilution. We study collapse in the denatured ensemble of single chain monellin (MNEI) using a coarse-grained protein model and molecular dynamics simulations. The model is validated by quantitatively comparing the computed Guanidinium Chloride (GuHCl) and pH-dependent thermodynamic properties of MNEI folding with the experiments. The computed properties such as the fraction of the protein in the folded state and radius of gyration (Rg) as function of [GuHCl] are in good agreement with the experiments...
September 15, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28921568/neuronal-activity-dependent-local-activation-of-dendritic-unfolded-protein-response-promotes-expression-of-brain-derived-neurotrophic-factor-in-cell-soma
#13
Atsushi Saito, Longjie Cai, Koji Matsuhisa, Yosuke Ohtake, Masayuki Kaneko, Soshi Kanemoto, Rie Asada, Kazunori Imaizumi
Unfolded protein response (UPR) has roles not only in resolving the accumulation of unfolded proteins owing to endoplasmic reticulum (ER) stress, but also in regulation of cellular physiological functions. ER stress transducers providing the branches of UPR signaling are known to localize in distal dendritic ER of neurons. These reports suggest that local activation of UPR branches may produce integrated outputs for distant communication, and allow regulation of local events in highly polarized neurons. Here, we demonstrated that synaptic activity- and brain-derived neurotrophic factor (BDNF)-dependent local activation of UPR signaling could be associated with dendritic functions through retrograde signal propagation by using murine neuroblastoma cell line, Neuro-2A and primary cultured hippocampal neurons derived from postnatal day 0 litter C57BL/6 mice...
September 16, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28921495/probing-rna-folding-pathways-by-rna-fingerprinting
#14
Sarah A Woodson
This unit provides protocols for using native polyacrylamide gel electrophoresis to distinguish folding and unfolding conformers of RNA. It is useful for studying conformers that can exchange in a period of minutes or seconds, and that are thus difficult to study by solution-based methods. Conformers that have been separated and immobilized in the gel matrix can be used to study catalytic activity with or without being eluted from the gel. The method can be applied to a wide variety of catalytic RNAs and RNA-protein complexes...
September 18, 2017: Current Protocols in Nucleic Acid Chemistry
https://www.readbyqxmd.com/read/28921106/kinetic-stability-of-membrane-proteins
#15
REVIEW
F Luis González Flecha
Although membrane proteins constitute an important class of biomolecules involved in key cellular processes, study of the thermodynamic and kinetic stability of their structures is far behind that of soluble proteins. It is known that many membrane proteins become unstable when removed by detergent extraction from the lipid environment. In addition, most of them undergo irreversible denaturation, even under mild experimental conditions. This process was found to be associated with partial unfolding of the polypeptide chain exposing hydrophobic regions to water, and it was proposed that the formation of kinetically trapped conformations could be involved...
September 18, 2017: Biophysical Reviews
https://www.readbyqxmd.com/read/28920507/navigating-the-structure-function-evolutionary-relationship-of-csaa-chaperone-in-archaea
#16
Archana Sharma, Shikha Rani, Manisha Goel
CsaA is a protein involved in the post-translational translocation of proteins across the cytoplasmic membrane. It is considered to be a functional homolog of SecB which participates in the Sec-dependent translocation pathway in an analogous manner. CsaA has also been reported to act as a molecular chaperone, preventing aggregation of unfolded proteins. It is essentially a prokaryotic protein which is absent in eukaryotes, but found extensively in bacteria and earlier thought to be widely present in archaea...
September 18, 2017: Critical Reviews in Microbiology
https://www.readbyqxmd.com/read/28919974/kinetic-and-thermodynamic-studies-reveal-chemokine-homologues-cc11-and-cc24-with-an-almost-identical-tertiary-structure-have-different-folding-pathways
#17
Baosheng Ge, Xiaoyong Jiang, Yao Chen, Tingting Sun, Qiuxia Yang, Fang Huang
BACKGROUND: Proteins with low sequence identity but almost identical tertiary structure and function have been valuable to uncover the relationship between sequence, tertiary structure, folding mechanism and functions. Two homologous chemokines, CCL11 and CCL24, with low sequence identity but similar tertiary structure and function, provide an excellent model system for respective studies. RESULTS: The kinetics and thermodynamics of the two homologous chemokines were systematically characterized...
2017: BMC Biophysics
https://www.readbyqxmd.com/read/28919078/slp1-emp65-a-guardian-factor-that-protects-folding-polypeptides-from-promiscuous-degradation
#18
Shan Zhang, Chengchao Xu, Katherine E Larrimore, Davis T W Ng
Newly synthesized proteins engage molecular chaperones that assist folding. Their progress is monitored by quality control systems that target folding errors for degradation. Paradoxically, chaperones that promote folding also direct unfolded polypeptides for degradation. Hence, a mechanism was previously hypothesized that prevents the degradation of actively folding polypeptides. In this study, we show that a conserved endoplasmic reticulum (ER) membrane protein complex, consisting of Slp1 and Emp65 proteins, performs this function in the ER lumen...
September 11, 2017: Cell
https://www.readbyqxmd.com/read/28917667/amyloid-%C3%AE-42-clearance-and-neuroprotection-mediated-by-x-box-binding-protein-1-signaling-decline-with-aging-in-the-drosophila-brain
#19
María S Marcora, Lautaro F Belfiori-Carrasco, Nadia I Bocai, Laura Morelli, Eduardo M Castaño
The unfolded protein response (UPR) may be pathogenically related to Alzheimer's disease. Yet, the effects of chronic amyloid-β42 (Aβ42) accumulation and UPR activation upon neurotoxicity remain unclear. Here, we show that neuronal Aβ42 expression in Drosophila activated the inositol-requiring protein-1/X-box binding protein 1 (XBP1) UPR branch before the onset of behavioral impairment and persisted with aging. Early upregulation of hsc3/BiP, a target of XBP1 and activating transcription factor 6 pathways, was also sustained in old animals...
August 24, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28917600/atp-alters-protein-folding-and-function-of-escherichia-coli-uridine-phosphorylase
#20
Yi-Kai Liu, Tzu-Hsuan Lin, Pei-Fen Liu
Uridine phosphorylase is one of the critical enzymes in the pyrimidine salvage pathway. Cells regenerate uridine for nucleotide metabolism by incorporating uracil with ribose-1-phosphate with this enzyme. Recent studies indicate that Escherichia coli uridine phosphorylase is destabilized in the presence of ATP. However, the mechanism underlying the destabilization process and its influence on uridine phosphorylase function remain to be established. Here, we comprehensively investigated the effects of ATP on protein folding and function of Escherichia coli uridine phosphorylase...
September 13, 2017: Archives of Biochemistry and Biophysics
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