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Unfolded Proteins

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https://www.readbyqxmd.com/read/28727885/sustained-activation-of-the-unfolded-protein-response-induces-cell-death-in-fuchs-endothelial-corneal-dystrophy
#1
Naoki Okumura, Miu Kitahara, Hirokazu Okuda, Keisuke Hashimoto, Emi Ueda, Makiko Nakahara, Shigeru Kinoshita, Robert D Young, Andrew J Quantock, Theofilos Tourtas, Ursula Schlötzer-Schrehardt, Friedrich Kruse, Noriko Koizumi
Purpose: The unfolded protein response (UPR) is believed to play a role in the pathogenesis of Fuchs' endothelial corneal dystrophy (FECD). The purpose of this study was to investigate whether unfolded proteins accumulate in the corneal endothelium in FECD and if they are involved in triggering cell death. Methods: Descemet's membranes with corneal endothelial cells (CECs) were obtained during keratoplasty, and expression of aggresomes, type 1 collagen, fibronectin, and agrin was evaluated...
July 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28726924/peculiarities-of-thermal-denaturation-of-ompf-porin-from-yersinia-ruckeri
#2
Olga D Novikova, Dmitry K Chistyulin, Valentina A Khomenko, Evgeny V Sidorin, Natalya Yu Kim, Nina M Sanina, Olga Yu Portnyagina, Tamara F Solov'eva, Vladimir N Uversky, Valery L Shnyrov
Irreversible denaturation of membrane proteins in detergent solutions is similar to unfolding of water-soluble multidomain proteins and represents a complex, multistage process. Pore-forming proteins of Gram-negative bacteria are heat-modifiable proteins, i.e., proteins altering their molecular forms (trimers or monomers), and accordingly, their electrophoretic mobilities depending upon denaturation conditions. There are still some contradictory data on the peculiarities of the conformational changes in the porin structure with temperature...
July 20, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28726407/residue-specific-interaction-of-an-unfolded-protein-with-solvents-in-mixed-water-ethanol-solutions-a-combined-molecular-dynamics-and-oniom-study
#3
Dayanidhi Mohanta, Santanu Santra, G Naaresh Reddy, Santanab Giri, Madhurima Jana
The molecular mechanism of ethanol governed unfolding of an enzymatic protein, Chymotripsin Inhibitor 2 (CI2) in water-ethanol mixed solutions has been studied by using combined Molecular Dynamics simulations and ONIOM study. The residue specific solvation of the unfolded protein and the interactions between the individual amino- acid residues of the protein with ethanol as well as water have been investigated. The results are compared with that obtained from the folded state of the protein. Further, emphasis has been given to explore the residue's preferential site of attraction towards the nature of the solvents...
July 20, 2017: Journal of Physical Chemistry. A
https://www.readbyqxmd.com/read/28725179/fine-tuning-er-stress-signal-transducers-to-treat-amyotrophic-lateral-sclerosis
#4
Danilo B Medinas, Jose V González, Paulina Falcon, Claudio Hetz
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motoneurons and paralysis. The mechanisms underlying neuronal degeneration in ALS are starting to be elucidated, highlighting disturbances in motoneuron proteostasis. Endoplasmic reticulum (ER) stress has emerged as an early pathogenic event underlying motoneuron vulnerability and denervation in ALS. Maintenance of ER proteostasis is controlled by a dynamic signaling network known as the unfolded protein response (UPR)...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28724906/reciprocal-carbonyl-carbonyl-interactions-in-small-molecules-and-proteins
#5
Abdur Rahim, Pinaki Saha, Kunal Kumar Jha, Nagamani Sukumar, Bani Kanta Sarma
Carbonyl-carbonyl n→π* interactions where a lone pair (n) of the oxygen atom of a carbonyl group is delocalized over the π* orbital of a nearby carbonyl group have attracted a lot of attention in recent years due to their ability to affect the 3D structure of small molecules, polyesters, peptides, and proteins. In this paper, we report the discovery of a "reciprocal" carbonyl-carbonyl interaction with substantial back and forth n→π* and π→π* electron delocalization between neighboring carbonyl groups...
July 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28724722/effect-of-directional-pulling-on-mechanical-protein-degradation-by-atp-dependent-proteolytic-machines
#6
Adrian O Olivares, Hema Chandra Kotamarthi, Benjamin J Stein, Robert T Sauer, Tania A Baker
AAA+ proteases and remodeling machines couple hydrolysis of ATP to mechanical unfolding and translocation of proteins following recognition of sequence tags called degrons. Here, we use single-molecule optical trapping to determine the mechanochemistry of two AAA+ proteases, Escherichia coli ClpXP and ClpAP, as they unfold and translocate substrates containing multiple copies of the titin(I27) domain during degradation initiated from the N terminus. Previous studies characterized degradation of related substrates with C-terminal degrons...
July 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28723893/in-vivo-crispr-screening-identifies-ptpn2-as-a-cancer-immunotherapy-target
#7
Robert T Manguso, Hans W Pope, Margaret D Zimmer, Flavian D Brown, Kathleen B Yates, Brian C Miller, Natalie B Collins, Kevin Bi, Martin W LaFleur, Vikram R Juneja, Sarah A Weiss, Jennifer Lo, David E Fisher, Diana Miao, Eliezer Van Allen, David E Root, Arlene H Sharpe, John G Doench, W Nicholas Haining
Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic screening approach using CRISPR-Cas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon-γ signalling caused resistance to immunotherapy...
July 19, 2017: Nature
https://www.readbyqxmd.com/read/28722205/temperature-stability-of-proteins-analysis-of-irreversible-denaturation-using-isothermal-calorimetry
#8
Arne Schön, Benjamin R Clarkson, Maria Jaime, Ernesto Freire
The structural stability of proteins has been traditionally studied under conditions in which the folding/unfolding reaction is reversible, since thermodynamic parameters can only be determined under these conditions. Achieving reversibility conditions in temperature stability experiments has often required performing the experiments at acidic pH or other non-physiological solvent conditions. With the rapid development of protein drugs, the fastest growing segment in the pharmaceutical industry, the need to evaluate protein stability under formulation conditions has acquired renewed urgency...
July 19, 2017: Proteins
https://www.readbyqxmd.com/read/28721412/effect-of-ligand-binding-on-a-protein-with-a-complex-folding-landscape
#9
Hisham Mazal, Haim Aviram, Inbal Riven, Gilad Haran
Ligand binding to a protein can stabilize it significantly against unfolding. The variation of the folding free energy, ΔΔG(0), due to ligand binding can be derived from a simple reaction scheme involving exclusive binding to the native state. One obtains the following expression: , where Kd is the ligand dissociation constant and L is its concentration, R is the universal gas constant and T is the temperature. This expression has been shown to correctly describe experimental results on multiple proteins...
July 19, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28720707/intrinsically-disordered-chromatin-protein-nupr1-binds-to-the-c-terminal-region-of-polycomb-ring1b
#10
Patricia Santofimia-Castaño, Bruno Rizzuti, Ángel L Pey, Philippe Soubeyran, Miguel Vidal, Raúl Urrutia, Juan L Iovanna, José L Neira
Intrinsically disordered proteins (IDPs) are ubiquitous in eukaryotes, and they are often associated with diseases in humans. The protein NUPR1 is a multifunctional IDP involved in chromatin remodeling and in the development and progression of pancreatic cancer; however, the details of such functions are unknown. Polycomb proteins are involved in specific transcriptional cascades and gene silencing. One of the proteins of the Polycomb complex is the Ring finger protein 1 (RING1). RING1 is related to aggressive tumor features in multiple cancer types...
July 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28719799/mesencephalic-astrocyte-derived-neurotrophic-factor-manf-a-new-player-in-endoplasmic-reticulum-diseases-structure-biology-and-therapeutic-roles
#11
REVIEW
Yeawon Kim, Sun-Ji Park, Ying Maggie Chen
Mesencephalic astrocyte-derived neurotrophic factor (MANF), a newly identified 18-kDa soluble protein, localizes to the luminal endoplasmic reticulum (ER), whose stress can stimulate MANF expression and secretion. In Drosophila and zebrafish, MANF regulates dopaminergic neuron development. In contrast, in mice, MANF deficiency leads to diabetes and activation of the unfolded protein response. Recent studies in rodent models have demonstrated that MANF mitigates diabetes, exerts neurotrophic function in neurodegenerative disease, protects cardiomyocytes and neurons in myocardial infarction and cerebral ischemia, respectively, and promotes immune cell phenotype switch from proinflammatory macrophages to prorepair anti-inflammatory macrophages...
June 29, 2017: Translational Research: the Journal of Laboratory and Clinical Medicine
https://www.readbyqxmd.com/read/28718844/solvent-gradient-electrospray-for-laser-ablation-electrospray-ionization-mass-spectrometry
#12
Hang Li, Akos Vertes
Most electrospray based ambient ionization techniques, e.g., laser ablation electrospray ionization (LAESI), utilize a fixed spray solution composition. Complex samples often contain compounds of different polarity that exhibit a wide range of solubilities in the electrospray solvent. Thus, the fixed spray solution composition limits the molecular coverage of these approaches. Two-barrel theta glass capillaries have been used for the rapid mixing of two solutions for manipulating fast reactions including protein folding, unfolding, and charge state distributions...
July 18, 2017: Analyst
https://www.readbyqxmd.com/read/28718404/emerging-role-of-the-unfolded-protein-response-in-tumor-immunosurveillance
#13
REVIEW
Hélène Vanacker, Jessica Vetters, Lyvia Moudombi, Christophe Caux, Sophie Janssens, Marie-Cécile Michallet
Disruption of endoplasmic reticulum (ER) homeostasis results in ER stress and activation of the unfolded protein response (UPR). This response alleviates cell stress, and is activated in both tumor cells and tumor infiltrating immune cells. The UPR plays a dual function in cancer biology, acting as a barrier to tumorigenesis at the premalignant stage, while fostering cancer maintenance in established tumors. In infiltrating immune cells, the UPR has been involved in both immunosurveillance and immunosuppressive functions...
July 2017: Trends in Cancer
https://www.readbyqxmd.com/read/28718225/proteostasis-and-ageing-insights-from-long-lived-mutant-mice
#14
William A Sands, Melissa M Page, Colin Selman
The global increase in life expectancy is creating significant medical, social and economic challenges to current and future generations. Consequently, there is a need to identify the fundamental mechanisms underlying the ageing process. This knowledge should help develop realistic interventions capable of combatting age-related disease, and thus improving late-life health and vitality. While several mechanisms have been proposed as conserved lifespan determinants, the loss of proteostasis- where proteostasis is defined here as the maintenance of the proteome- appears highly relevant to both ageing and disease...
July 17, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28716919/decoupling-of-size-and-shape-fluctuations-in-heteropolymeric-sequences-reconciles-discrepancies-in-saxs-vs-fret-measurements
#15
Gustavo Fuertes, Niccolò Banterle, Kiersten M Ruff, Aritra Chowdhury, Davide Mercadante, Christine Koehler, Michael Kachala, Gemma Estrada Girona, Sigrid Milles, Ankur Mishra, Patrick R Onck, Frauke Gräter, Santiago Esteban-Martín, Rohit V Pappu, Dmitri I Svergun, Edward A Lemke
Unfolded states of proteins and native states of intrinsically disordered proteins (IDPs) populate heterogeneous conformational ensembles in solution. The average sizes of these heterogeneous systems, quantified by the radius of gyration (RG ), can be measured by small-angle X-ray scattering (SAXS). Another parameter, the mean dye-to-dye distance (RE ) for proteins with fluorescently labeled termini, can be estimated using single-molecule Förster resonance energy transfer (smFRET). A number of studies have reported inconsistencies in inferences drawn from the two sets of measurements for the dimensions of unfolded proteins and IDPs in the absence of chemical denaturants...
July 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28716186/formation-of-protein-surfactant-adsorption-layer-as-studied-by-dilational-surface-rheology
#16
REVIEW
Boris A Noskov, Michael M Krycki
The review discusses the mechanism of formation of protein/surfactant adsorption layers at the liquid - gas interface. The complexes of globular proteins usually preserve their compact structure a low surfactant concentrations. Therefore a simple kinetic model of the adsorption of charged compact nanoparticles is discussed first and compared with experimental data. The increase of surfactant concentrations results in various conformational transitions in the surface layer. One can obtain information on the changes of the adsorption layer structure using the dilational surface rheology...
July 6, 2017: Advances in Colloid and Interface Science
https://www.readbyqxmd.com/read/28714684/the-surface-of-protein-%C3%AE-6-85-can-act-as-a-template-for-recurring-peg-structure
#17
Shu-Han Chao, Jan Schaefer, Martin Gruebele
PEGylated proteins play an increasingly important role in pharmaceutical drug delivery. We recently showed that short PEG chains can affect protein structure, even when they are not making extensive contact with the protein surface. In contrast, PEG is generally assumed to form a relatively unstructured coil, whose compactness depends on solvent conditions. Here we test whether a host protein could allow PEG to form recurrent structural motifs while the PEG chain is in contact with the protein surface. We link a PEG oligomer (n=45) to one of two nearly opposite locations on the small alpha-helical protein 6-85 to investigate this question...
July 17, 2017: Biochemistry
https://www.readbyqxmd.com/read/28714672/chemical-denaturants-smoothen-ruggedness-on-the-free-energy-landscape-of-protein-folding
#18
Pooja Malhotra, Prashant Navalbhai Jethva, Jayant B Udgaonkar
To characterize experimentally the ruggedness of the free energy landscape of protein folding is challenging, because the distributed small free energy barriers are usually dominated by one or a few, large activation free energy barriers. The present study delineates changes in the roughness of the free energy landscape by making use of the observation that a decrease in ruggedness is accompanied invariably by an increase in folding cooperativity. Hydrogen exchange coupled to mass spectrometry (HX-MS) was used to detect transient sampling of local energy minima and the global unfolded state on the free energy landscape of the small protein, single chain monellin...
July 17, 2017: Biochemistry
https://www.readbyqxmd.com/read/28713984/downregulation-of-microrna%C3%A2-199a%C3%A2-5p-protects-cardiomyocytes-in-cyanotic-congenital-heart-disease-by-attenuating-endoplasmic-reticulum-stress
#19
Yang Zhou, Wei-Kun Jia, Zhao Jian, Liang Zhao, Chen-Cheng Liu, Yong Wang, Ying-Bin Xiao
Chronic hypoxia is a key pathological change in patients with cyanotic congenital heart defect (CCHD). It has been demonstrated that enhanced myocardial unfolded protein response (UPR) increases the capacity to buffer endoplasmic reticulum (ER) stress and to avoid subsequent apoptosis caused by the hypoxia that underlies CCHD. The present study was performed to determine the regulatory role of microRNAs (miRNAs) in this cytoprotective UPR process. The results revealed that miR‑199a‑5p was markedly downregulated in the cardiac tissue of patients with CCHD and in human myocardial cells cultured in hypoxic conditions...
July 6, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28713242/the-distance-between-n-and-c-termini-of-tau-and-of-ftdp-17-mutants-is-modulated-by-microtubule-interactions-in-living-cells
#20
Cristina Di Primio, Valentina Quercioli, Giacomo Siano, Matteo Rovere, Branislav Kovacech, Michal Novak, Antonino Cattaneo
The microtubule (MT)-associated protein Tau is a natively unfolded protein, involved in a number of neurodegenerative disorders, collectively called tauopathies, aggregating in neurofibrillary tangles (NFT). It is an open question how the conversion from a MT bound molecule to an aggregation-prone Tau species occurs and, also, if and how tauopathy-related mutations affect its behavior in the cell. To address these points, we exploited a genetically encoded FRET sensor based on the full length Tau protein, to monitor in real time Tau conformational changes in different conditions in live cells...
2017: Frontiers in Molecular Neuroscience
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