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Unfolded Proteins

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https://www.readbyqxmd.com/read/28431320/trehalose-supplementation-reduces-hepatic-endoplasmic-reticulum-stress-and-inflammatory-signaling-in-old-mice
#1
Michael J Pagliassotti, Andrea L Estrada, William M Hudson, Yuren Wei, Dong Wang, Douglas R Seals, Melanie L Zigler, Thomas J LaRocca
The accumulation of damaged proteins can perturb cellular homeostasis and provoke aging and cellular damage. Quality control systems, such as the unfolded protein response (UPR), inflammatory signaling and protein degradation, mitigate the residence time of damaged proteins. In the present study, we have examined the UPR and inflammatory signaling in the liver of young (~6 months) and old (~28 months) mice (n=8/group), and the ability of trehalose, a compound linked to increased protein stability and autophagy, to counteract age-induced effects on these systems...
April 6, 2017: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/28430857/repurposed-drugs-targeting-eif2%C3%AE-p-mediated-translational-repression-prevent-neurodegeneration-in-mice
#2
Mark Halliday, Helois Radford, Karlijn A M Zents, Collin Molloy, Julie A Moreno, Nicholas C Verity, Ewan Smith, Catharine A Ortori, David A Barrett, Martin Bushell, Giovanna R Mallucci
Signalling through the PERK/eIF2α-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is overactivated in brains of patients with Alzheimer's disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions. Thus, in mouse models of neurodegenerative disease, prolonged overactivation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss...
April 19, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28430800/the-burden-of-trisomy-21-disrupts-the-proteostasis-network-in-down-syndrome
#3
Stefanos Aivazidis, Christina M Coughlan, Abhishek K Rauniyar, Hua Jiang, L Alexander Liggett, Kenneth N Maclean, James R Roede
Down syndrome (DS) is a genetic disorder caused by trisomy of chromosome 21. Abnormalities in chromosome number have the potential to lead to disruption of the proteostasis network (PN) and accumulation of misfolded proteins. DS individuals suffer from several comorbidities, and we hypothesized that disruption of proteostasis could contribute to the observed pathology and decreased cell viability in DS. Our results confirm the presence of a disrupted PN in DS, as several of its elements, including the unfolded protein response, chaperone system, and proteasomal degradation exhibited significant alterations compared to euploid controls in both cell and mouse models...
2017: PloS One
https://www.readbyqxmd.com/read/28429799/expression-control-of-the-ampk-regulatory-subunit-and-its-functional-significance-in-yeast-er-stress-response
#4
Yuichi Kimura, Kenji Irie, Tomoaki Mizuno
AMP-activated protein kinase (AMPK) is an evolutionarily conserved heterotrimeric kinase complex consisting of a catalytic subunit, α, and two regulatory subunits, β and γ. Previously, we demonstrated that Snf1, the Saccharomyces cerevisiae ortholog of AMPK, negatively regulates the unfolded protein response (UPR) pathway and the Hog1 MAP kinase pathway in ER stress response. However, it remains unclear how the alternate three β subunits, Sip1, Sip2, and Gal83, of the Snf1 complex participate in ER stress response...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28429276/enhancing-thermal-stability-of-a-highly-concentrated-insulin-formulation-with-pluronic-f-127-for-long-term-use-in-microfabricated-implantable-devices
#5
Jason Li, Michael K Chu, Brian Lu, Sako Mirzaie, Kuan Chen, Claudia R Gordijo, Oliver Plettenburg, Adria Giacca, Xiao Yu Wu
Development of highly concentrated formulations of protein and peptide drugs is a major challenge due to increased susceptibility to aggregation and precipitation. Numerous drug delivery systems including implantable and wearable controlled-release devices require thermally stable formulations with high concentrations due to limited device sizes and long-term use. Herein we report a highly concentrated insulin gel formulation (up to 80 mg/mL, corresponding to 2200 IU/mL), stabilized with a non-ionic amphiphilic triblock copolymer (i...
April 20, 2017: Drug Delivery and Translational Research
https://www.readbyqxmd.com/read/28429159/a-brief-history-of-the-discovery-of-the-mitochondrial-unfolded-protein-response-in-mammalian-cells
#6
Nick Hoogenraad
Cells have responded to stresses which cause proteins to come out of solution by evolving unfolded protein response mechanisms. In eukaryotic cells there are several such mechanisms covering the whole cell and sub-celllular organelles. This review describes discoveries that describe the unfolded protein response in the matrix compartment of mitochondria (mtUPRR) of mammalian cells.
April 20, 2017: Journal of Bioenergetics and Biomembranes
https://www.readbyqxmd.com/read/28428045/sco2-deficient-mice-develop-increased-adiposity-and-insulin-resistance
#7
Shauna Hill, Sathyaseelan S Deepa, Kavithalakshmi Sataranatarajan, Pavithra Premkumar, Daniel Pulliam, Yuhong Liu, Vanessa Y Soto, Kathleen E Fischer, Holly Van Remmen
Cytochrome c oxidase (COX) is an essential transmembrane protein complex (Complex IV) in the mitochondrial respiratory electron chain. Mutations in genes responsible for the assembly of COX are associated with Leigh syndrome, cardiomyopathy, spinal muscular atrophy and other fatal metabolic disorders in humans. Previous studies have shown that mice lacking the COX assembly protein Surf1 (Surf1(-/-) mice) paradoxically show a number of beneficial metabolic phenotypes including increased insulin sensitivity, upregulation of mitochondrial biogenesis, induction of stress response pathways and increased lifespan...
April 17, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28427262/melting-proteins-evidence-for-multiple-stable-structures-upon-thermal-denaturation-of-native-ubiquitin-from-ims-ms-measurements
#8
Tarick J El-Baba, Daniel W Woodall, Shannon A Raab, Daniel R Fuller, Arthur Laganowsky, David H Russell, David E Clemmer
Ion mobility and mass spectrometry techniques have been coupled with a new temperature-controlled electrospray ionization source in order to follow the structural transitions of ubiquitin in aqueous solution (pH = 3) at elevated solution temperatures (T = 26 to 96 °C). Changes in the charge state distribution are consistent with a two-state, cooperative unfolding transition having a melting temperature of Tm = 71 ± 2 °C, in agreement with prior calorimetric measurements [Wintrode, P. L.; Makhatadze, G. I...
April 20, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28425717/an-experimental-and-molecular-dynamics-study-of-red-fluorescent-protein-mcherry-in-novel-aqueous-amino-acid-ionic-liquids
#9
Kelsey L Borrell, Christine Cancglin, Brittany L Stinger, Kelsey G DeFrates, Gregory A Caputo, Chun Wu, Timothy D Vaden
The search for biocompatible ionic liquids (ILs) with novel biochemical and biomedical applications has recently gained greater attention. In this report we characterize the effects of two novel amino acid-based aqueous ILs composed of tetramethylguanidinium (TMG) and amino acids on the structure and stability of a widely used red fluorescent protein (mCherry). Our experimental data shows that while the aspartic acid-based IL (TMGAsp) has effects similar to previously-studied conventional ILs (BMIBF4, EMIAc, and TMGAc), the alanine-based IL (TMGAla) has a much stronger destabilization effect on the protein structure...
April 20, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28425289/imaging-metastable-states-and-transitions-in-proteins-by-trajectory-map
#10
Chuanbiao Zhang, Jin Yu, Xin Zhou
It has been a long-standing and intriguing issue to develop robust methods to identify metastable states and interstate transitions from simulations or experimental data in order to understand the functional conformational changes of proteins. Most of the existing methods are usually hard to define the complicated boundaries of the states in the conformational space, and thus often lead to parameter-sensitive results. Here we present a new approach, named as visualized Trajectory Map (vTM), to identify the metastable states and the rare interstate transitions, by considering both the conformation similarity and the temporal-successiveness of conformations...
April 20, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28424579/grp78-at-the-centre-of-the-stage-in-cancer-and-neuroprotection
#11
REVIEW
Caty Casas
The 78-kDa glucose-regulated protein GRP78, also known as BiP and HSP5a, is a multifunctional protein with activities far beyond its well-known role in the unfolded protein response (UPR) which is activated after endoplasmic reticulum (ER) stress in the cells. Most of these newly discovered activities depend on its position within the cell. GRP78 is located mainly in the ER, but it has also been observed in the cytoplasm, the mitochondria, the nucleus, the plasma membrane, and secreted, although it is dedicated mostly to engage endogenous cytoprotective processes...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28424476/neurons-export-extracellular-vesicles-enriched-in-cysteine-string-protein-and-misfolded-protein-cargo
#12
Jingti Deng, Carolina Koutras, Julien Donnelier, Mana Alshehri, Maryam Fotouhi, Martine Girard, Steve Casha, Peter S McPherson, Stephen M Robbins, Janice E A Braun
The fidelity of synaptic transmission depends on the integrity of the protein machinery at the synapse. Unfolded synaptic proteins undergo refolding or degradation in order to maintain synaptic proteostasis and preserve synaptic function, and buildup of unfolded/toxic proteins leads to neuronal dysfunction. Many molecular chaperones contribute to proteostasis, but one in particular, cysteine string protein (CSPα), is critical for proteostasis at the synapse. In this study we report that exported vesicles from neurons contain CSPα...
April 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28424159/prolonged-elimination-of-negative-feedback-control-mechanisms-along-the-insulin-signalling-pathway-impairs-%C3%AE-cell-function-in-vivo
#13
Roi Isaac, Yaron Vinik, Sigalit Boura-Halfon, Lydia Farack, Sarina Streim, Eytan Elhanany, Zvi Kam, Yehiel Zick
Cellular stress and pro-inflammatory cytokines induce phosphorylation of insulin receptor substrate (IRS) proteins at Ser sites that inhibit insulin and IGF-1 signalling. We therefore examined the effects of mutation of five 'inhibitory' Ser phosphorylation sites on IRS2 function in transgenic mice that overexpress, selectively in pancreatic β cells, either wild-type (WT) or a mutated IRS2 protein (IRS2(5A)). Islets size, number, and mRNA levels of catalase and superoxide dismutase, were increased, while those of nitric oxide synthase were decreased in 7-10 weeks old IRS2(5A)-β mice compared to IRS2(WT)-β mice...
April 19, 2017: Diabetes
https://www.readbyqxmd.com/read/28423937/concordance-of-several-subcellular-interactions-initiates-alzheimer-s-dementia-their-reversal-requires-combination-treatment
#14
W J Fessel
The pathogenesis of Alzheimer's disease involves multiple pathways that, at the macrolevel, include decreased proliferation plus increased loss affecting neurons, astrocytes, and capillaries and, at the subcellular level, involve several elements: amyloid/amyloid precursor protein, presenilins, the unfolded protein response, the ubiquitin/proteasome system, the Wnt/catenin system, the Notch signaling system, mitochondria, mitophagy, calcium, and tau. Data presented show the intimate, anatomical interactions between neurons, astrocytes, and capillaries; the interactions between the several subcellular factors affecting those cells; and the treatments that are currently available and that might correct dysfunctions in the subcellular factors...
May 2017: American Journal of Alzheimer's Disease and Other Dementias
https://www.readbyqxmd.com/read/28423909/ripping-rna-by-force-using-gaussian-network-models
#15
Changbong Hyeon, D Thirumalai
Using force as a probe to map the folding landscapes of RNA molecules has become a reality thanks to major advances in single molecule pulling experiments. Although the unfolding pathways under tension are complicated to predict, studies in the context of proteins have shown that topology is the major determinant of the unfolding landscapes. By building on this finding we study the responses of RNA molecules to force by adapting Gaussian network model (GNM) that represents RNAs using a bead-spring network with isotropic interactions...
April 20, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28423644/disulfide-bond-disrupting-agents-activate-the-unfolded-protein-response-in-egfr-and-her2-positive-breast-tumor-cells
#16
Renan B Ferreira, Mengxiong Wang, Mary E Law, Bradley J Davis, Ashton N Bartley, Paul J Higgins, Michael S Kilberg, Katherine E Santostefano, Naohiro Terada, Coy D Heldermon, Ronald K Castellano, Brian K Law
Many breast cancer deaths result from tumors acquiring resistance to available therapies. Thus, new therapeutic agents are needed for targeting drug-resistant breast cancers. Drug-refractory breast cancers include HER2+ tumors that have acquired resistance to HER2-targeted antibodies and kinase inhibitors, and "Triple-Negative" Breast Cancers (TNBCs) that lack the therapeutic targets Estrogen Receptor, Progesterone Receptor, and HER2. A significant fraction of TNBCs overexpress the HER2 family member Epidermal Growth Factor Receptor (EGFR)...
March 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423496/mtor-inhibitors-activate-perk-signaling-and-favor-viability-of-gastrointestinal-neuroendocrine-cell-lines
#17
Patricia Freis, Julien Bollard, Justine Lebeau, Patrick Massoma, Joëlle Fauvre, Cécile Vercherat, Thomas Walter, Serge Manié, Colette Roche, Jean-Yves Scoazec, Carole Ferraro-Peyret
mTOR and Unfolded Protein Response (UPR) are two signaling pathways frequently activated in cancer cells. The mTOR pathway has been shown to be up-regulated in most gastroenteropancreatic neuroendocrine tumors. In contrast, little is known about the UPR status in neoplastic neuroendocrine cells. However, these hormone-producing cells are likely to present distinctive adaptations of this pathway, as other secretory cells. We therefore analyzed the status of the three axes of UPR and their relation to mTOR pathway in two gastrointestinal neuroendocrine tumors (GI-NET) cell lines STC-1 and GluTag...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28422069/protein-stability-and-unfolding-following-glycine-radical-formation
#18
Michael C Owen, Imre G Csizmadia, Béla Viskolcz, Birgit Strodel
Glycine (Gly) residues are particularly susceptible to hydrogen abstraction; which results in the formation of the capto-dative stabilized Cα-centered Gly radical (GLR) on the protein backbone. We examined the effect of GLR formation on the structure of the Trp cage; tryptophan zipper; and the villin headpiece; three fast-folding and stable miniproteins; using all-atom (OPLS-AA) molecular dynamics simulations. Radicalization changes the conformation of the GLR residue and affects both neighboring residues but did not affect the stability of the Trp zipper...
April 19, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28421184/the-proteasomal-atpases-use-a-slow-but-highly-processive-strategy-to-unfold-proteins
#19
Aaron Snoberger, Raymond T Anderson, David M Smith
All domains of life have ATP-dependent compartmentalized proteases that sequester their peptidase sites on their interior. ATPase complexes will often associate with these compartmentalized proteases in order to unfold and inject substrates into the protease for degradation. Significant effort has been put into understanding how ATP hydrolysis is used to apply force to proteins and cause them to unfold. The unfolding kinetics of the bacterial ATPase, ClpX, have been shown to resemble a fast motor that traps unfolded intermediates as a strategy to unfold proteins...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/28421160/the-unfolded-protein-response-at-the-intersection-between-endoplasmic-reticulum-function-and-mitochondrial-bioenergetics
#20
REVIEW
Amado Carreras-Sureda, Philippe Pihán, Claudio Hetz
Endoplasmic reticulum (ER) to mitochondria communication has emerged in recent years as a signaling hub regulating cellular physiology with a relevant contribution to diseases including cancer and neurodegeneration. This functional integration is exerted through discrete interorganelle structures known as mitochondria-associated membranes (MAMs). At these domains, ER/mitochondria physically associate to dynamically adjust metabolic demands and the response to stress stimuli. Here, we provide a focused overview of how the ER shapes the function of the mitochondria, giving a special emphasis to the significance of local signaling of the unfolded protein response at MAMs...
2017: Frontiers in Oncology
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