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https://www.readbyqxmd.com/read/28230968/inhibition-of-%C3%AE-synuclein-fibril-elongation-by-hsp70-is-governed-by-a-kinetic-binding-competition-between-%C3%AE-synuclein-species
#1
Francesco A Aprile, Paolo Arosio, Giuliana Fusco, Serene W Chen, Janet R Kumita, Anne Dhulesia, Paolo Tortora, Tuomas P J Knowles, Michele Vendruscolo, Christopher M Dobson, Nunilo Cremades
The Hsp70 family of chaperones plays an essential role in suppressing protein aggregation in the cell. Here we investigate the factors controlling the intrinsic ability of human Hsp70 to inhibit the elongation of amyloid fibrils formed by the Parkinson's disease-related protein α-synuclein. Using kinetic analysis, we show that Hsp70 binds preferentially to α-synuclein fibrils as a consequence of variations in the association and dissociation rate constants of binding to the different aggregated states of the protein...
February 23, 2017: Biochemistry
https://www.readbyqxmd.com/read/28230282/ablation-of-cyclophilin-d-results-in-an-activation-of-fak-akt-and-erk-pathways-in-the-mouse-heart
#2
Jelena Klawitter, Tamas Seres, Alexander Pennington, Jonathan-Thomas Beatty, Jost Klawitter, Uwe Christians
Cyclophilin D (CypD) is a mitochondrial chaperone that regulates the mitochondrial permeability transition pore. Metabolically, deletion of Ppif (the gene encoding CypD) in mice is associated with elevated levels of mitochondrial matrix Ca(2+) that leads to increased glucose as relative to fatty acid oxidation. Here, we characterized the adaptive mechanisms involved in the regulation of glucose metabolism including the regulation of Akt and ERK kinases that we evaluated by Western blot analysis of Ppif-/-in comparison to wild type (WT) mouse hearts...
February 23, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28228754/proofreading-of-peptide-mhc-complexes-through-dynamic-multivalent-interactions
#3
REVIEW
Christoph Thomas, Robert Tampé
The adaptive immune system is able to detect and destroy cells that are malignantly transformed or infected by intracellular pathogens. Specific immune responses against these cells are elicited by antigenic peptides that are presented on major histocompatibility complex class I (MHC I) molecules and recognized by cytotoxic T lymphocytes at the cell surface. Since these MHC I-presented peptides are generated in the cytosol by proteasomal protein degradation, they can be metaphorically described as a window providing immune cells with insights into the state of the cellular proteome...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28228012/investigation-of-thermally-induced-cellular-ablation-and-heat-response-triggered-by-planar-mos2-based-nanocomposite
#4
Shinya Ariyasu, Jing Mu, Xiao Zhang, Ying Huang, Edwin K L Yeow, Hua Zhang, Bengang Xing
In comparison to conventional tumor treatment methods, photothermal therapy (PTT) is one of the innovative therapeutic strategies that employs light to produce the localized heat for targeted ablation of cancer cells. Among various kinds of heat generation nanomaterials, transition metal dichalcogenide nanosheets, especially-molybdenum disulfide (MoS2) have recently been investigated as one of the promising PTT candidates because of their strong absorbance in the near-infrared (NIR) tissue transparency window and excellent photothermal conversion capability...
February 23, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28225177/an-irreversible-inhibitor-of-hsp72-that-unexpectedly-targets-lysine-56
#5
Jonathan Pettinger, Yann-Vaï Le Bihan, Marcella Widya, Rob L M van Montfort, Keith Jones, Matthew D Cheeseman
The stress-inducible molecular chaperone, HSP72, is an important therapeutic target in oncology, but inhibiting this protein with small molecules has proven particularly challenging. Validating HSP72 inhibitors in cells is difficult owing to competition with the high affinity and abundance of its endogenous nucleotide substrates. We hypothesized this could be overcome using a cysteine-targeted irreversible inhibitor. Using rational design, we adapted a validated 8-N-benzyladenosine ligand for covalent bond formation and confirmed targeted irreversible inhibition...
February 22, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28224655/rna-seq-analysis-of-transcriptional-change-in-the-freshwater-mussel-elliptio-complanata-after-environmentally-relevant-sodium-chloride-exposure
#6
Laura S Robertson, Heather S Galbraith, Deborah Iwanowicz, Carrie J Blakeslee, R Scott Cornman
To identify potential biomarkers of salt stress in a freshwater sentinel species, we examined transcriptional responses of the common mussel Elliptio complanata to controlled NaCl exposures. RNA-Seq of mantle tissue identified 481 transcripts differentially expressed in adult mussels exposed to 2 ppt NaCl (1.2 ppt chloride) for seven days, of which 290 had non-overlapping intervals. Differentially expressed gene categories included ion and transmembrane transport, oxidoreductase activity, maintenance of protein folding, and amino acid metabolism...
February 22, 2017: Environmental Toxicology and Chemistry
https://www.readbyqxmd.com/read/28223916/the-emerging-roles-of-early-protein-folding-events-in-the-secretory-pathway-in-the-development-of-neurodegenerative-maladies
#7
REVIEW
Tatyana Dubnikov, Ehud Cohen
Although, protein aggregation and deposition are unifying features of various neurodegenerative disorders, recent studies indicate that different mechanisms can lead to the development of the same malady. Among these, failure in early protein folding and maturation emerge as key mechanistic events that lead to the manifestation of a myriad of illnesses including Alzheimer's disease and prion disorders. Here we delineate the cascade of maturation steps that nascent polypeptides undergo in the secretory pathway to become functional proteins, and the chaperones that supervise and assist this process, focusing on the subgroup of proline cis/trans isomerases...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28223360/a-novel-subtilase-inhibitor-in-plants-shows-structural-and-functional-similarities-to-protease-propeptides
#8
Mathias Hohl, Annick Stintzi, Andreas Schaller
The propeptides of subtilisin-like serine proteinases (SBTs) serve dual functions as intramolecular chaperones that are required for enzyme folding and as inhibitors of the mature proteases. SBT propeptides are homologous to the I9 family of protease inhibitors that have only been described in fungi. Here we report the identification and characterization of Subtilisin Propeptide-Like Inhibitor 1 (SPI-1) from Arabidopsis thaliana. Sequence similarity and the shared β-α-β-β-α-β core structure identified SPI-1 as a member of the I9 inhibitor family, and as the first independent I9 inhibitor in higher eukaryotes...
February 21, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28222009/alzheimer-s-and-danish-dementia-peptides-induce-cataract-and-perturb-retinal-architecture-in-rats
#9
G Bhanuprakash Reddy, P Yadagiri Reddy, Avadhesha Surolia
Familial Danish dementias (FDDs) are autosomal dominant neurodegenerative disorders that are associated with visual defects. In some aspects, FDD is similar to Alzheimer's disease (AD)- the amyloid deposits in FDD and AD are made of short peptides: amyloid β (Aβ) in AD and ADan in FDD. Previously, we demonstrated an interaction between the dementia peptides and α-crystallin leading to lens opacification in organ culture due to impaired chaperone activity of α-crystallin. Herein, we report the in vivo effects of ADan and Aβ on the eye...
February 21, 2017: Biomolecular Concepts
https://www.readbyqxmd.com/read/28221352/dynamic-undocking-and-the-quasi-bound-state-as-tools-for-drug-discovery
#10
Sergio Ruiz-Carmona, Peter Schmidtke, F Javier Luque, Lisa Baker, Natalia Matassova, Ben Davis, Stephen Roughley, James Murray, Rod Hubbard, Xavier Barril
There is a pressing need for new technologies that improve the efficacy and efficiency of drug discovery. Structure-based methods have contributed towards this goal but they focus on predicting the binding affinity of protein-ligand complexes, which is notoriously difficult. We adopt an alternative approach that evaluates structural, rather than thermodynamic, stability. As bioactive molecules present a static binding mode, we devised dynamic undocking (DUck), a fast computational method to calculate the work necessary to reach a quasi-bound state at which the ligand has just broken the most important native contact with the receptor...
March 2017: Nature Chemistry
https://www.readbyqxmd.com/read/28220836/nucleobindin-1-binds-to-multiple-types-of-pre-fibrillar-amyloid-and-inhibits-fibrillization
#11
Alessandra Bonito-Oliva, Shahar Barbash, Thomas P Sakmar, W Vallen Graham
During amyloid fibril formation, amyloidogenic polypeptides misfold and self assemble into soluble pre-fibrillar aggregates, i.e., protofibrils, which elongate and mature into insoluble fibrillar aggregates. An emerging class of chaperones, chaperone-like amyloid binding proteins (CLABPs), has been shown to interfere with aggregation of particular misfolded amyloid peptides or proteins. We have discovered that the calcium-binding protein nuclebindin-1 (NUCB1) is a novel CLABP. We show that NUCB1 inhibits aggregation of islet-amyloid polypeptide associated with type 2 diabetes mellitus, a-synuclein associated with Parkinson's disease, transthyretin V30M mutant associated with familial amyloid polyneuropathy, and Aβ42 associated with Alzheimer's disease by stabilizing their respective protofibril intermediates...
February 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28220688/the-dnaj-protein-osdja6-negatively-regulates-rice-innate-immunity-to-the-blast-fungus-magnaporthe-oryzae
#12
Xionghui Zhong, Jiuxia Yang, Yanlong Shi, Xuli Wang, Guo-Liang Wang
Rice blast, caused by Magnaporthe oryzae (synonym: Pyricularia oryzae), severely reduces rice production and grain quality. The molecular mechanism of rice resistance to M. oryzae is not fully understood. In the present study, we identified a chaperone DnaJ protein, OsDjA6, that is involved in basal resistance to M. oryzae in rice. The OsDjA6 protein is distributed in the entire rice cell. The expression of OsDjA6 is significantly induced in rice after infection with a compatible isolate. Silencing of OsDjA6 in transgenic rice enhances resistance to M...
February 21, 2017: Molecular Plant Pathology
https://www.readbyqxmd.com/read/28220454/the-remarkable-multivalency-of-the-hsp70-chaperones
#13
REVIEW
Erik R P Zuiderweg, Lawrence E Hightower, Jason E Gestwicki
Hsp70 proteins are key to maintaining intracellular protein homeostasis. To carry out this task, they employ a large number of cochaperones and adapter proteins. Here, we review what is known about the interaction between the chaperones and partners, with a strong slant toward structural biology. Hsp70s in general, and Hsc70 (HSPA8) in particular, display an amazing array of interfaces with their protein cofactors. We also review the known interactions between Hsp70s with lipids and with active compounds that may become leads toward Hsp70 modulation for treatment of a variety of diseases...
February 20, 2017: Cell Stress & Chaperones
https://www.readbyqxmd.com/read/28219929/hsp70-displaces-small-heat-shock-proteins-from-aggregates-to-initiate-protein-refolding
#14
Szymon Żwirowski, Agnieszka Kłosowska, Igor Obuchowski, Nadinath B Nillegoda, Artur Piróg, Szymon Ziętkiewicz, Bernd Bukau, Axel Mogk, Krzysztof Liberek
Small heat shock proteins (sHsps) are an evolutionary conserved class of ATP-independent chaperones that protect cells against proteotoxic stress. sHsps form assemblies with aggregation-prone misfolded proteins, which facilitates subsequent substrate solubilization and refolding by ATP-dependent Hsp70 and Hsp100 chaperones. Substrate solubilization requires disruption of sHsp association with trapped misfolded proteins. Here, we unravel a specific interplay between Hsp70 and sHsps at the initial step of the solubilization process...
February 20, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28219790/subunit-specific-synaptic-delivery-of-ampa-receptors-by-auxiliary-chaperone-proteins-tarp%C3%AE-8-and-gsg1l-in-classical-conditioning
#15
Joyce Keifer, Neeraj K Tiwari, Leah Buse, Zhaoqing Zheng
AMPA receptor (AMPAR) trafficking has emerged as a fundamental concept for understanding mechanisms of learning and memory as well as many neurological disorders. Classical conditioning is a simple and highly conserved form of associative learning. Our studies use an ex vivo brainstem preparation in which to study cellular mechanisms underlying learning during a neural correlate of eyeblink conditioning. Two stages of AMPAR synaptic delivery underlie conditioning utilizing sequential trafficking of GluA1-containing AMPARs early in conditioning followed by replacement with GluA4 subunits later...
February 17, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28219205/-preparation-of-chaperone-antigen-peptide-vaccine-derived-from-human-gastric-cancer-stem-cells-and-its-immune-function
#16
Y Q Jiang, Q M Guo, X P Xu, J C Liang, Y Y He, S H An, F Su, C Y Li, C X Huang
Objective: To explore the method of extracting chaperone antigen peptide complexes from gastric cancer stem cells and its immune function. Methods: Gastric cancer stem cells and gastric cancer cells were screened by low temperature ultrasonic lysis. After salting out and dialysis, the lysate supernatant was processed with SDS-PAGE to analyze the expression of chaperone antigen peptide complexes, and then was separated and purified with CNBr-activated SepharoseTM 4B. Reverse high pressure liquid chromatography (HPLC), SDS-PAGE and Western blotting were used to analyze the purity and nature of the acquired albumen...
February 23, 2017: Zhonghua Zhong Liu za Zhi [Chinese Journal of Oncology]
https://www.readbyqxmd.com/read/28218913/ligand-promoted-protein-folding-by-biased-kinetic-partitioning
#17
Karan S Hingorani, Matthew C Metcalf, Derrick T Deming, Scott C Garman, Evan T Powers, Lila M Gierasch
Protein folding in cells occurs in the presence of high concentrations of endogenous binding partners, and exogenous binding partners have been exploited as pharmacological chaperones. A combined mathematical modeling and experimental approach shows that a ligand improves the folding of a destabilized protein by biasing the kinetic partitioning between folding and alternative fates (aggregation or degradation). Computationally predicted inhibition of test protein aggregation and degradation as a function of ligand concentration are validated by experiments in two disparate cellular systems...
February 20, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28218749/mechanistic-basis-for-the-recognition-of-a-misfolded-protein-by-the-molecular-chaperone-hsp90
#18
Javier Oroz, Jin Hae Kim, Bliss J Chang, Markus Zweckstetter
The critical toxic species in over 40 human diseases are misfolded proteins. Their interaction with molecular chaperones such as Hsp90, which preferentially interacts with metastable proteins, is essential for the blocking of disease progression. Here we used nuclear magnetic resonance (NMR) spectroscopy to determine the three-dimensional structure of the misfolded cytotoxic monomer of the amyloidogenic human protein transthyretin, which is characterized by the release of the C-terminal β-strand and perturbations of the A-B loop...
February 20, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28218284/proteomic-analysis-of-exported-chaperone-co-chaperone-complexes-of-p-falciparum-reveals-an-array-of-complex-protein-protein-interactions
#19
Qi Zhang, Cheng Ma, Alexander Oberli, Astrid Zinz, Sonja Engels, Jude M Przyborski
Malaria parasites modify their human host cell, the mature erythrocyte. This modification is mediated by a large number of parasite proteins that are exported to the host cell, and is also the underlying cause for the pathology caused by malaria infection. Amongst these proteins are many Hsp40 co-chaperones, and a single Hsp70. These proteins have been implicated in several processes in the host cell, including a potential role in protein transport, however the further molecular players in this process remain obscure...
February 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28218250/chromatin-remodeller-fun30-fft3-induces-nucleosome-disassembly-to-facilitate-rna-polymerase-ii-elongation
#20
Junwoo Lee, Eun Shik Choi, Hogyu David Seo, Keunsoo Kang, Joshua M Gilmore, Laurence Florens, Michael P Washburn, Joonho Choe, Jerry L Workman, Daeyoup Lee
Previous studies have revealed that nucleosomes impede elongation of RNA polymerase II (RNAPII). Recent observations suggest a role for ATP-dependent chromatin remodellers in modulating this process, but direct in vivo evidence for this is unknown. Here using fission yeast, we identify Fun30(Fft3) as a chromatin remodeller, which localizes at transcribing regions to promote RNAPII transcription. Fun30(Fft3) associates with RNAPII and collaborates with the histone chaperone, FACT, which facilitates RNAPII elongation through chromatin, to induce nucleosome disassembly at transcribing regions during RNAPII transcription...
February 20, 2017: Nature Communications
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