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Unfolded Proteins

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https://www.readbyqxmd.com/read/29782836/dancing-with-the-diva-hsp90-client-interactions
#1
REVIEW
Martina Radli, Stefan G D Rüdiger
The molecular chaperone Hsp90 is involved in the folding, maturation and degradation of a large number structurally and sequentially unrelated clients, often connected to serious diseases. Elucidating the principles of how Hsp90 recognises this large variety of substrates is essential for comprehending the mechanism of this chaperone machinery, as well as it is a prerequisite for the design of client specific drugs targeting Hsp90. Here, we discuss the recent progress in understanding the substrate recognition principles of Hsp90 and its implications for the role of Hsp90 in the lifecycle of (signalling) molecules...
May 18, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29780480/on-chip-measurements-of-protein-unfolding-from-direct-observations-of-micron-scale-diffusion
#2
Yuewen Zhang, Emma V Yates, Liu Hong, Kadi L Saar, Georg Meisl, Christopher M Dobson, Tuomas P J Knowles
Investigations of protein folding, unfolding and stability are critical for the understanding of the molecular basis of biological structure and function. We describe here a microfluidic approach to probe the unfolding of unlabelled protein molecules in microliter volumes. We achieve this objective through the use of a microfluidic platform, which allows the changes in molecular diffusivity upon folding and unfolding to be detected directly. We illustrate this approach by monitoring the unfolding of bovine serum albumin in solution as a function of pH...
April 14, 2018: Chemical Science
https://www.readbyqxmd.com/read/29780459/folding-mechanisms-steer-the-amyloid-fibril-formation-propensity-of-highly-homologous-proteins
#3
Gaetano Malgieri, Gianluca D'Abrosca, Luciano Pirone, Angelo Toto, Maddalena Palmieri, Luigi Russo, Michele Francesco Maria Sciacca, Rosarita Tatè, Valeria Sivo, Ilaria Baglivo, Roksana Majewska, Massimo Coletta, Paolo Vincenzo Pedone, Carla Isernia, Mario De Stefano, Stefano Gianni, Emilia Maria Pedone, Danilo Milardi, Roberto Fattorusso
Significant advances in the understanding of the molecular determinants of fibrillogenesis can be expected from comparative studies of the aggregation propensities of proteins with highly homologous structures but different folding pathways. Here, we fully characterize, by means of stopped-flow, T-jump, CD and DSC experiments, the unfolding mechanisms of three highly homologous proteins, zinc binding Ros87 and Ml153-149 and zinc-lacking Ml452-151 . The results indicate that the three proteins significantly differ in terms of stability and (un)folding mechanisms...
April 7, 2018: Chemical Science
https://www.readbyqxmd.com/read/29780350/alpha-synuclein-from-early-synaptic-dysfunction-to-neurodegeneration
#4
REVIEW
Veronica Ghiglieri, Valeria Calabrese, Paolo Calabresi
Over the last two decades, many experimental and clinical studies have provided solid evidence that alpha-synuclein (α-syn), a small, natively unfolded protein, is closely related to Parkinson's disease (PD) pathology. To provide an overview on the different roles of this protein, here we propose a synopsis of seminal and recent studies that explored the many aspects of α-syn. Ranging from the physiological functions to its neurodegenerative potential, the relationship with the possible pathogenesis of PD will be discussed...
2018: Frontiers in Neurology
https://www.readbyqxmd.com/read/29779477/exposure-of-aggregation-prone-segments-is-the-requirement-for-amyloid-fibril-formation
#5
Shreya Pramanik, Basir Ahmad
Arranging into well-organized fibrillar aggregate, commonly known as amyloid fibril is an inherent property of any polypeptide chain. Amyloid fibrils are associated with a number of severe human pathologies like the Alzheimer's disease, Parkinson's disease, type2 diabetes and many more. Recent studies suggest that most of the fibrils are inert and extremely stable, thus could be used for the bio-nanotechnological applications. As the native state is protected by evolution from aggregation under physiological condition, understanding the structure of aggregation precursor state (APS) will be of extreme importance to decode mechanism of its formation and prevention...
May 20, 2018: Current Protein & Peptide Science
https://www.readbyqxmd.com/read/29777695/proteasome-mediated-protein-degradation-is-enhanced-by-fusion-ubiquitin-with-unstructured-degron
#6
Tomonao Inobe, Masayuki Tsukamoto, Miyuki Nozaki
Methods to induce proteasomal degradation of unwanted proteins are valuable in biomedical studies and thus receive increasing attention. For efficient degradation, the proteasome requires both a ubiquitin tag, which delivers substrates to the proteasome, and an unstructured region, where the proteasome engages the substrate for unfolding and degradation. We fused two degron components into a single molecule to create a fusion protein comprising ubiquitin and Rpn4-derived unstructured region. We demonstrated that the fusion protein retained its function to polyubiquitinate target proteins, thereby inducing more efficient proteasomal target degradation than wild-type ubiquitin in vitro and in cells...
May 16, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29777685/thiamine-preserves-mitochondrial-function-in-a-rat-model-of-traumatic-brain-injury-preventing-inactivation-of-the-2-oxoglutarate-dehydrogenase-complex
#7
Garik V Mkrtchyan, Muammer Üçal, Andrea Müllebner, Sergiu Dumitrescu, Martina Kames, Rudolf Moldzio, Marek Molcanyi, Samuel Schaefer, Adelheid Weidinger, Ute Schaefer, Juergen Hescheler, Johanna Catharina Duvigneau, Heinz Redl, Victoria I Bunik, Andrey V Kozlov
BACKGROUND AND PURPOSE: Based on the fact that traumatic brain injury is associated with mitochondrial dysfunction we aimed at localization of mitochondrial defect and attempted to correct it by thiamine. EXPERIMENTAL APPROACH: Interventional controlled experimental animal study was used. Adult male Sprague-Dawley rats were subjected to lateral fluid percussion traumatic brain injury. Thiamine was administered 1 h prior to trauma; cortex was extracted for analysis 4 h and 3 d after trauma...
May 16, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29776093/impact-of-hydrodynamic-interactions-on-protein-folding-rates-depends-on-temperature
#8
Fabio C Zegarra, Dirar Homouz, Yossi Eliaz, Andrei G Gasic, Margaret S Cheung
We investigated the impact of hydrodynamic interactions (HI) on protein folding using a coarse-grained model. The extent of the impact of hydrodynamic interactions, whether it accelerates, retards, or has no effect on protein folding, has been controversial. Together with a theoretical framework of the energy landscape theory (ELT) for protein folding that describes the dynamics of the collective motion with a single reaction coordinate across a folding barrier, we compared the kinetic effects of HI on the folding rates of two protein models that use a chain of single beads with distinctive topologies: a 64-residue α/β chymotrypsin inhibitor 2 (CI2) protein, and a 57-residue β-barrel α-spectrin Src-homology 3 domain (SH3) protein...
March 2018: Physical Review. E
https://www.readbyqxmd.com/read/29774376/roles-of-heat-shock-factor-1-beyond-the-heat-shock-response
#9
REVIEW
János Barna, Péter Csermely, Tibor Vellai
Various stress factors leading to protein damage induce the activation of an evolutionarily conserved cell protective mechanism, the heat shock response (HSR), to maintain protein homeostasis in virtually all eukaryotic cells. Heat shock factor 1 (HSF1) plays a central role in the HSR. HSF1 was initially known as a transcription factor that upregulates genes encoding heat shock proteins (HSPs), also called molecular chaperones, which assist in refolding or degrading injured intracellular proteins. However, recent accumulating evidence indicates multiple additional functions for HSF1 beyond the activation of HSPs...
May 17, 2018: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29773650/the-exercise-inducible-bile-acid-receptor-tgr5-improves-skeletal-muscle-function-in-mice
#10
Takashi Sasaki, Ayane Kuboyama, Moeko Mita, Shotaro Murata, Makoto Shimizu, Jun Inoue, Kazutoshi Mori, Ryuichiro Sato
TGR5 (also known as G protein-coupled bile acid receptor 1, GPBAR1) is a G protein-coupled bile acid receptor that is expressed in many diverse tissues. TGR5 is involved in various metabolic processes, including glucose metabolism and energy expenditure; however, TGR5's function in skeletal muscle is not fully understood. Using both gain- and loss-of-function mouse models, we demonstrate here that Tgr5 activation promotes muscle cell differentiation and muscle hypertrophy. Both young and old transgenic mice with muscle-specific Tgr5 expression exhibited increased muscle strength...
May 17, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29773177/participation-of-selenoproteins-localized-in-the-er-in-the-processes-occurring-in-this-organelle-and-in-the-regulation-of-carcinogenesis-associated-processes
#11
REVIEW
Elena Gennadyevna Varlamova
The functions performed by the ER are diverse: synthesis of steroid hormones, synthesis of proteins for the plasma membrane, lysosomes, as well as proteins meant for exocytosis, protein folding, formation of disulfide bonds, N-linked glycosylation, etc. Selenoproteins localized in this organelle are definitely involved in the processes occurring in it, and the most common of them include participation in protein degradation, regulation of ER stress and redox metabolism. ER stress has been registered in many types of cancer cells...
July 2018: Journal of Trace Elements in Medicine and Biology
https://www.readbyqxmd.com/read/29772680/the-crosstalk-of-endoplasmic-reticulum-er-stress-pathways-with-nf-%C3%AE%C2%BAb-complex-mechanisms-relevant-for-cancer-inflammation-and-infection
#12
REVIEW
M Lienhard Schmitz, M Samer Shaban, B Vincent Albert, Anke Gökçen, Michael Kracht
Stressful conditions occuring during cancer, inflammation or infection activate adaptive responses that are controlled by the unfolded protein response (UPR) and the nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) signaling pathway. These systems can be triggered by chemical compounds but also by cytokines, toll-like receptor ligands, nucleic acids, lipids, bacteria and viruses. Despite representing unique signaling cascades, new data indicate that the UPR and NF-κB pathways converge within the nucleus through ten major transcription factors (TFs), namely activating transcription factor (ATF)4, ATF3, CCAAT/enhancer-binding protein (CEBP) homologous protein (CHOP), X-box-binding protein (XBP)1, ATF6α and the five NF-κB subunits...
May 16, 2018: Biomedicines
https://www.readbyqxmd.com/read/29771603/negative-feedback-loop-of-autophagy-and-endoplasmic-reticulum-stress-in-rapamycin-protection-against-renal-ischemia-reperfusion-injury-during-initial-reperfusion-phase
#13
Xinyuan Li, Gongmin Zhu, Xin Gou, Weiyang He, Hubin Yin, Xiaoyu Yang, Jie Li
Rapamycin, an immunosuppressant, is widely used in patients with kidney transplant. However, the therapeutic effects of rapamycin remain controversial. Additionally, previous studies have revealed deleterious effects of rapamycin predominantly when administered for ≥24 h. Few studies, however, have focused on the short-term effects of rapamycin administered only during the initial reperfusion phase. As such, we designed this study to explore the potential effects and mechanisms of rapamycin under a specific therapeutic regimen in which rapamycin is mixed in the perfusate during the initial reperfusion phase (within 24 h)...
May 17, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29771522/hydronium-ions-accompanying-buried-acidic-residues-lead-to-high-apparent-dielectric-constants-in-the-interior-of-proteins
#14
Xiongwu Wu, Bernard R Brooks
Internal ionizable groups are known to play important roles in protein functions. A mystery that has attracted decades of extensive experimental and theoretical studies is the apparent dielectric constants experienced by buried ionizable groups, which are much higher than values expected for protein interiors. Many interpretations have been proposed, such as water penetration, conformational relaxation, local unfolding, protein intrinsic backbone fluctuations, etc. However, these interpretations conflict with many experimental observations...
May 17, 2018: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/29771510/relevance-of-the-speed-and-direction-of-pulling-in-simple-modular-proteins
#15
Carlos A Plata, Zackary N Scholl, Piotr E Marszalek, Antonio Prados
A theoretical framework capable of predicting the first unit that unfolds in pulled modular proteins has been recently introduced, for "fast enough" pulling velocities. Within this picture, we investigate the unfolding pathway in a chain of identical units and predict that the module closest to the pulled end opens first. Steered molecular dynamics of a simple construct, specifically a chain composed of two coiled-coil motives, shows that this is indeed the case. Notwithstanding, the unfolding behavior strongly depends on the terminus (C or N) from which this homopolyprotein is pulled...
May 17, 2018: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/29770126/crosstalk-between-the-unfolded-protein-response-micrornas-and-insulin-signaling-pathways-in-search-of-biomarkers-for-the-diagnosis-and-treatment-of-type-2-diabetes
#16
REVIEW
Chinar Berry, Megha Lal, B K Binukumar
Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by functional defects in glucose metabolism and insulin secretion. Its complex etiology and multifaceted nature have made it difficult to design effective therapies for early diagnosis and treatment. Several lines of evidence indicate that aberrant activation of the unfolded protein response (UPR) in response to endoplasmic reticulum (ER) stress impairs the β cell's ability to respond to glucose and promotes apoptosis. Elucidating the molecular mechanisms that govern β cell dysfunction and cell death can help investigators design therapies to halt or prevent the development of T2DM...
2018: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/29769338/the-perk-arm-of-the-unfolded-protein-response-negatively-regulates-transmissible-gastroenteritis-virus-replication-by-suppressing-protein-translation-and-promoting-type-i-ifn-production
#17
Mei Xue, Fang Fu, Yanlong Ma, Xin Zhang, Liang Li, Li Feng, Pinghuang Liu
Coronavirus replication is closely associated with the endoplasmic reticulum (ER), the primary cellular organelle for protein synthesis, folding, and modification. ER stress is a common consequence in coronavirus-infected cells. However, how the virus-induced ER stress influences coronavirus replication and pathogenesis remains controversial. Here, we demonstrated that infection with the alphacoronavirus transmissible gastroenteritis virus (TGEV) induced ER stress and triggered the unfolded protein response (UPR) in vitro and in vivo , and ER stress negatively regulated TGEV replication in vitro Although TGEV infection activated all three UPR pathways (ATF6, IRE1, and PERK), the virus-triggered UPR suppressed TGEV replication in both ST and IPEC-J2 cells primarily through activation of the PERK-eIF2α axis, as shown by functional studies with overexpression, siRNA, or specific chemical inhibitors...
May 16, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29769316/the-serine-threonine-protein-kinase-endoribonuclease-ire1%C3%AE-protects-the-heart-against-pressure-overload-induced-heart-failure
#18
DeAnna Steiger, Tomohiro Yokota, Jin Li, Shuxun Ren, Susumu Minamisawa, Yibin Wang
Heart failure is associated with induction of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). The serine/threonine protein kinase/endoribonuclease IRE1α is a key protein in ER stress signal transduction. IRE1α activity can induce both protective UPR and apoptotic downstream signaling events, but the specific role for IRE1α activity in the heart is unknown. A major aim of this study was to characterize the specific contribution of IRE1α in cardiac physiology and pathogenesis. We used both cultured myocytes and a transgenic mouse line with inducible and cardiomyocyte-specific IRE1α overexpression as experimental models to achieve targeted IRE1α activation...
May 16, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29767978/dynamics-of-ionic-liquids-assisted-refolding-of-denatured-cytochrome-c-a-study-of-preferential-interactions-towards-renaturation
#19
Upendra Kumar Singh, Rajan Patel
In vitro refolding of denatured proteins and influence of alkyl chain of these organic salts on their performance as refolding enhancers was tested using long chain imidazolium chloride salts, 1-methyl-3-octylimidazolium chloride [C8mim][Cl], 1-decyl-3-methylimidazolium chloride [C10mim][Cl]. The horse heart cytochrome c (h-cyt c) was denatured by urea and guanidinium hydrochloride (GdnHCl), as well as base induced denaturation at pH 13 to provide a broad overview of the overall refolding behavior. The variation in alkyl chain of ionic liquids (ILs) showed a profound effect on the refolding of denatured h-cyt c...
May 16, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29766802/endoplasmic-reticulum-stress-related-molecular-mechanisms-in-nonalcoholic-fatty-liver-disease-nafld
#20
Lifeng Wang, Jun Ren
Non-alcoholic fatty liver disease (NAFLD) has emerged as a common public health problem and a common cause of chronic liver diseases. However, the underlying mechanisms leading to the development and progression of NAFLD remain elusive. Accumulating evidence has depicted an essential role for endoplasmic reticulum (ER) stress in the development of steatosis and later progression into nonalcoholic steatohepatitis and hepatocarcinoma. With the accumulation of unfolded and misfolded proteins in the ER lumen, ER stress is provoked to turn on the unfolded protein response (UPR)...
May 16, 2018: Current Drug Targets
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