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Unfolded Proteins

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https://www.readbyqxmd.com/read/29149522/melatonin-improves-the-meiotic-maturation-of-porcine-oocytes-by-reducing-endoplasmic-reticulum-stress-during-in-vitro-maturation
#1
Hyo-Jin Park, Jae-Young Park, Jin-Woo Kim, Seul-Gi Yang, Jae-Min Jung, Min-Ji Kim, Man-Jong Kang, Young Ho Cho, Gabbine Wee, Hee-Young Yang, Bong-Seok Song, Sun-Uk Kim, Deog-Bon Koo
Under endoplasmic reticulum (ER)-stress conditions, the unfolded protein response (UPR) generates a defense mechanism in mammalian cells. The regulation of UPR signaling is important in oocyte maturation, embryo development, and female reproduction of pigs. Recent studies have shown that melatonin plays an important role as an anti-oxidant to improve pig oocyte maturation. However, there is no report on the role of melatonin in the regulation of UPR signaling and ER-stress during in vitro maturation (IVM) of porcine oocytes...
November 17, 2017: Journal of Pineal Research
https://www.readbyqxmd.com/read/29148236/emerging-roles-of-er-stress-in-the-aetiology-and-pathogenesis-of-alzheimer-s-disease
#2
REVIEW
Yannis Gerakis, Claudio Hetz
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by synaptic dysfunction and accumulation of abnormal aggregates formed by amyloid-β peptides or phophorylated Tau proteins. Accumulating evidence suggests that alterations in the buffering capacity of the proteostasis network is a salient feature of AD. The endoplasmic reticulum (ER) is the main compartment involved in protein folding and secretion and is drastically affected in AD neurons. ER stress triggers the activation of the Unfolded Protein Response (UPR), a signal transduction pathway that enforces adaptive programs to recover homeostasis or trigger apoptosis of irreversibly damaged cells...
November 17, 2017: FEBS Journal
https://www.readbyqxmd.com/read/29146980/the-energy-cost-of-polypeptide-knot-formation-and-its-folding-consequences
#3
Andrés Bustamante, Juan Sotelo-Campos, Daniel G Guerra, Martin Floor, Christian M A Wilson, Carlos Bustamante, Mauricio Báez
Knots are natural topologies of chains. Yet, little is known about spontaneous knot formation in a polypeptide chain-an event that can potentially impair its folding-and about the effect of a knot on the stability and folding kinetics of a protein. Here we used optical tweezers to show that the free energy cost to form a trefoil knot in the denatured state of a polypeptide chain of 120 residues is 5.8 ± 1 kcal mol(-1). Monte Carlo dynamics of random chains predict this value, indicating that the free energy cost of knot formation is of entropic origin...
November 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/29146369/dose-dependent-effects-of-rosmarinic-acid-on-formation-of-oxidatively-stressed-myofibrillar-protein-emulsion-gel-at-different-nacl-concentrations
#4
Shuangxi Wang, Yumeng Zhang, Lin Chen, Xinglian Xu, Guanghong Zhou, Zhixi Li, Xianchao Feng
The effects of rosmarinic acid (RA) (12, 60 and 300μM/g protein) on the textural properties and stability of oxidized myofibrillar protein (MP) emulsion gels were investigated. A low dose (12µM/g) of RA significantly prevented the loss of thiol and ε-NH2 groups and the unfolding of the oxidized MP. However, a high dose of RA (300µM/g) covalently and non-covalently interacted with the MPs, which induced a significant loss of thiol and ε-NH2 groups and aggregation of the MPs, causing decreased solubility, resulting in a poor three-dimensional emulsion gel network, and hence, higher cooking loss and lower gel strength...
March 15, 2018: Food Chemistry
https://www.readbyqxmd.com/read/29145850/targeting-protein-quality-control-pathways-in-breast-cancer
#5
REVIEW
Sara Sannino, Jeffrey L Brodsky
The efficient production, folding, and secretion of proteins is critical for cancer cell survival. However, cancer cells thrive under stress conditions that damage proteins, so many cancer cells overexpress molecular chaperones that facilitate protein folding and target misfolded proteins for degradation via the ubiquitin-proteasome or autophagy pathway. Stress response pathway induction is also important for cancer cell survival. Indeed, validated targets for anti-cancer treatments include molecular chaperones, components of the unfolded protein response, the ubiquitin-proteasome system, and autophagy...
November 16, 2017: BMC Biology
https://www.readbyqxmd.com/read/29145399/point-mutation-in-d8c-domain-of-tamm-horsfall-protein-uromodulin-in-transgenic-mice-causes-progressive-renal-damage-and-hyperuricemia
#6
Lijie Ma, Yan Liu, Nichole K Landry, Tarek M El-Achkar, John C Lieske, Xue-Ru Wu
Hereditary mutations in Tamm-Horsfall protein (THP/uromodulin) gene cause autosomal dominant kidney diseases characterized by juvenile-onset hyperuricemia, gout and progressive kidney failure, although the disease pathogenesis remains unclear. Here we show that targeted expression in transgenic mice of a mutation within the domain of 8 cysteines of THP in kidneys' thick ascending limb (TAL) caused unfolded protein response in younger (1-month old) mice and apoptosis in older (12-month old) mice. While the young mice had urine concentration defects and polyuria, such defects progressively reversed in the older mice to marked oliguria, highly concentrated urine, fibrotic kidneys and reduced creatinine clearance...
2017: PloS One
https://www.readbyqxmd.com/read/29142472/prostaglandin-e1-protects-hepatocytes-against-endoplasmic-reticulum-stress-induced-apoptosis-via-protein-kinase-a-dependent-induction-of-glucose-regulated-protein-78-expression
#7
Fang-Wan Yang, Yu Fu, Ying Li, Yi-Huai He, Mao-Yuan Mu, Qi-Chuan Liu, Jun Long, Shi-De Lin
AIM: To investigate the protective effect of prostaglandin E1 (PGE1) against endoplasmic reticulum (ER) stress-induced hepatocyte apoptosis, and to explore its underlying mechanisms. METHODS: Thapsigargin (TG) was used to induce ER stress in the human hepatic cell line L02 and hepatocarcinoma-derived cell line HepG2. To evaluate the effects of PGE1 on TG-induced apoptosis, PGE1 was used an hour prior to TG treatment. Activation of unfolded protein response signaling pathways were detected by western blotting and quantitative real-time RT-PCR...
October 28, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29141431/development-of-isothermal-isobaric-replica-permutation-method-for-molecular-dynamics-and-monte-carlo-simulations-and-its-application-to-reveal-temperature-and-pressure-dependence-of-folded-misfolded-and-unfolded-states-of-chignolin
#8
Masataka Yamauchi, Hisashi Okumura
We developed a two-dimensional replica-permutation molecular dynamics method in the isothermal-isobaric ensemble. The replica-permutation method is a better alternative to the replica-exchange method. It was originally developed in the canonical ensemble. This method employs the Suwa-Todo algorithm, instead of the Metropolis algorithm, to perform permutations of temperatures and pressures among more than two replicas so that the rejection ratio can be minimized. We showed that the isothermal-isobaric replica-permutation method performs better sampling efficiency than the isothermal-isobaric replica-exchange method and infinite swapping method...
November 14, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/29141194/marginal-stability-drives-irreversible-unfolding-of-large-multi-domain-family-3-glycosylhydrolases-from-thermo-tolerant-yeast
#9
Mohammad Asif Shah, Saroj Mishra, Tapan Kumar Chaudhuri
Protein folding is an extremely complex and fast, yet perfectly defined process, involving interplay of many intra and inter-molecular forces. In vitro, these molecular interactions are reversible for many proteins e.g., smaller and monomeric, organized into single domains. However, refolding of larger multi-domain/multimeric proteins is much more complicated, proceeds in a hierarchal way and is often irreversible. In a comparative study on two large, multi-domain and multimeric isozymes, β -glucosidase I (BGLI) and β-glucosidase II (BGLII) from Pichia etchellsii, we studied spontaneous and assisted refolding under three denaturing conditions viz...
November 12, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/29141152/tm-values-and-unfolded-fraction-can-predict-aggregation-rates-for-gcsf-variant-formulations-but-not-under-predominantly-native-conditions
#10
Mathew J Robinson, Paul Matejtschuk, Adrian F Bristow, Paul A Dalby
Protein engineering and formulation optimisation strategies can be taken to minimise protein aggregation in the biopharmaceutical industry. Short-term stability measures such as the mid-point transition temperature (Tm) for global unfolding provide convenient surrogates for longer-term (eg 2-year) degradation kinetics, with which to optimise formulations on practical time-scales. While successful in some cases, their limitations have not been fully evaluated or understood. Tm values are known to correlate with chemical degradation kinetics for wild-type granulocyte colony stimulating factor (GCSF) at pH 4-5...
November 15, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29138881/a-harmonized-immunoassay-with-liquid-chromatography-mass-spectrometry-analysis-in-egg-allergen-determination
#11
Masaomi Nimata, Hideki Okada, Kei Kurihara, Tsukasa Sugimoto, Tsutomu Honjoh, Kazuhiko Kuroda, Takeo Yano, Hirofumi Tachibana, Masahiro Shoji
Food allergy is a serious health issue worldwide. Implementing allergen labeling regulations is extremely challenging for regulators, food manufacturers, and analytical kit manufacturers. Here we have developed an "amino acid sequence immunoassay" approach to ELISA. The new ELISA comprises of a monoclonal antibody generated via an analyte specific peptide antigen and sodium lauryl sulfate/sulfite solution. This combination enables the antibody to access the epitope site in unfolded analyte protein. The newly developed ELISA recovered 87...
November 14, 2017: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/29138281/a-conserved-cytoskeletal-signaling-cascade-mediates-neurotoxicity-of-ftdp-17-tau-mutations-in-vivo
#12
Farah H Bardai, Liqun Wang, Yamini Mutreja, Mythili Yenjerla, T Chris Gamblin, Mel B Feany
The microtubule binding protein tau is strongly implicated in multiple neurodegenerative disorders, including frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), which is caused by mutations in tau. In vitro, FTDP-17 mutant versions of tau can reduce microtubule binding and increase aggregation of tau, but the mechanism by which these mutations promote disease in vivo is not clear. Here we take a combined biochemical and in vivo modeling approach to define functional properties of tau driving neurotoxicity in vivo We express wild type human tau and five FTDP-17 mutant forms of tau in Drosophila using a site-directed insertion strategy to ensure equivalent levels of expression...
November 14, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29138095/kinetics-and-thermodynamics-of-the-thermal-inactivation-and-chaperone-assisted-folding-of-zebrafish-dihydrofolate-reductase
#13
Charu Thapliyal, Neha Jain, Naira Rashid, Pratima Chaudhuri
The maintenance of thermal stability is a major issue in protein engineering as many proteins tend to form inactive aggregates at higher temperatures. Zebrafish DHFR, an essential protein for the survival of cells, shows irreversible thermal unfolding transition. The protein exhibits complete unfolding and loss of activity at 50 °C as monitored by UV-Visible, fluorescence and far UV-CD spectroscopy. The heat induced inactivation of zDHFR follows first-order kinetics and Arrhenius law. The variation in the value of inactivation rate constant, k with increasing temperatures depicts faster inactivation at elevated temperatures...
November 11, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/29138002/the-mechanism-of-hdea-unfolding-and-chaperone-activation
#14
Loïc Salmon, Frederick Stull, Sabrina Sayle, Claire Cato, Şerife Akgül, Linda Foit, Logan S Ahlstrom, Elan Z Eisenmesser, Hashim M Al-Hashimi, James C A Bardwell, Scott Horowitz
HdeA is a periplasmic chaperone that is rapidly activated upon shifting the pH to acidic conditions. This activation is thought to involve monomerization of HdeA. There is evidence that monomerization and partial unfolding allow the chaperone to bind to proteins denatured by low pH thereby protecting them from aggregation. We analyzed the acid-induced unfolding of HdeA using NMR spectroscopy and fluorescence measurements, and obtained experimental evidence suggesting a complex mechanism in HdeA's acid-induced unfolding pathway, as previously postulated from molecular dynamics simulations...
November 11, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29137221/anti-pancreatic-cancer-activity-of-onc212-involves-the-unfolded-protein-response-upr-and-is-reduced-by-igf1-r-and-grp78-bip
#15
Avital Lev, Amriti R Lulla, Jessica Wagner, Marie D Ralff, Joshua B Kiehl, Yan Zhou, Cyril H Benes, Varun V Prabhu, Wolfgang Oster, Igor Astsaturov, David T Dicker, Wafik S El-Deiry
Pancreatic cancer is chemo-resistant and metastasizes early with an overall five-year survival of ∼8.2%. First-in-class imipridone ONC201 is a small molecule in clinical trials with anti-cancer activity. ONC212, a fluorinated-ONC201 analogue, shows preclinical efficacy in melanoma and hepatocellular-cancer models. We investigated efficacy of ONC201 and ONC212 against pancreatic cancer cell lines (N=16 including 9 PDX-cell lines). We demonstrate ONC212 efficacy in 4 in-vivo models including ONC201-resistant tumors...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29136510/genomic-subtypes-of-non-invasive-bladder-cancer-with-distinct-metabolic-profile-and-female-gender-bias-in-kdm6a-mutation-frequency
#16
Carolyn D Hurst, Olivia Alder, Fiona M Platt, Alastair Droop, Lucy F Stead, Julie E Burns, George J Burghel, Sunjay Jain, Leszek J Klimczak, Helen Lindsay, Jo-An Roulson, Claire F Taylor, Helene Thygesen, Angus J Cameron, Anne J Ridley, Helen R Mott, Dmitry A Gordenin, Margaret A Knowles
Bladder cancer incurs a higher lifetime treatment cost than other cancers due to frequent recurrence of non-invasive disease. Improved prognostic biomarkers and localized therapy are needed for this large patient group. We defined two major genomic subtypes of primary stage Ta tumors. One of these was characterized by loss of 9q including TSC1, increased KI67 labeling index, upregulated glycolysis, DNA repair, mTORC1 signaling, features of the unfolded protein response, and altered cholesterol homeostasis. Comparison with muscle-invasive bladder cancer mutation profiles revealed lower overall mutation rates and more frequent mutations in RHOB and chromatin modifier genes...
November 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29132128/a-single-cysteine-post-translational-oxidation-suffices-to-compromise-globular-proteins-kinetic-stability-and-promote-amyloid-formation
#17
Patrizia Marinelli, Susanna Navarro, Ricardo Graña-Montes, Manuel Bañó-Polo, María Rosario Fernández, Elena Papaleo, Salvador Ventura
Oxidatively modified forms of proteins accumulate during aging. Oxidized protein conformers might act as intermediates in the formation of amyloids in age-related disorders. However, it is not known whether this amyloidogenic conversion requires an extensive protein oxidative damage or it can be promoted just by a discrete, localized post-translational modification of certain residues. Here, we demonstrate that the irreversible oxidation of a single free Cys suffices to severely perturb the folding energy landscape of a stable globular protein, compromise its kinetic stability, and lead to the formation of amyloids under physiological conditions...
October 31, 2017: Redox Biology
https://www.readbyqxmd.com/read/29131589/using-tryptophan-mutants-to-probe-the-structural-and-functional-status-of-bssco-a-copper-binding-cytochrome-c-oxidase-assembly-protein-from-bacillus-subtilis
#18
Shina Hussain, Diann Andrews, Bruce C Hill
The synthesis of cytochrome c oxidase protein from Bacillus subtilis (i.e., BsSCO) binds copper with picomolar affinity, which increases the protein's melting temperature (i.e., TM) by 20 °C. Here two native tryptophans (i.e., W36 and W101) are identified as major contributors to BsSCO's structural form, and their contributions to the stability, intrinsic fluorescence, and copper binding properties of BsSCO are explored. Single mutations of tryptophan to phenylalanine decrease the TM by 10 °C and the folding free energy by 3-4 kcal/mol...
November 17, 2017: Biochemistry
https://www.readbyqxmd.com/read/29129774/crosstalk-between-endoplasmic-reticulum-stress-and-brain-inflammation-in-alzheimer-s-disease
#19
REVIEW
Luis E Santos, Sergio T Ferreira
While most often noted for its cognitive symptoms, Alzheimer's disease (AD) is, at its core, a disease of protein misfolding/aggregation, with an intriguing inflammatory component. Defective clearance and/or abnormal production of the amyloid-β peptide (Aβ), and its ensuing accumulation and aggregation, underlie two hallmark features of AD: brain accumulation of insoluble protein deposits known as amyloid or senile plaques, and buildup of soluble Aβ oligomers (AβOs), diffusible toxins linked to synapse dysfunction and memory impairment...
November 9, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/29129755/phylogenetic-analysis-predicts-structural-divergence-for-proteobacterial-clpc-proteins
#20
Justin M Miller, Hamza Chaudhary, Justin D Marsee
Regulated proteolysis is required in all organisms for the removal of misfolded or degradation-tagged protein substrates in cellular quality control pathways. The molecular machines that catalyze this process are known as ATP-dependent proteases with examples that include ClpAP and ClpCP. Clp/Hsp100 subunits form ring-structures that couple the energy of ATP binding and hydrolysis to protein unfolding and subsequent translocation of denatured protein into the compartmentalized ClpP protease for degradation...
November 9, 2017: Journal of Structural Biology
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