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Unfolded Proteins

Jeffrey K Holden, Christian N Cunningham
The Hippo pathway is a critical transcriptional signaling pathway that regulates cell growth, proliferation and organ development. The transcriptional enhanced associate domain (TEAD) protein family consists of four paralogous transcription factors that function to modulate gene expression in response to the Hippo signaling pathway. Transcriptional activation of these proteins occurs upon binding to the co-activator YAP/TAZ whose entry into the nucleus is regulated by Lats1/2 kinase. In recent years, it has become apparent that the dysregulation and/or overexpression of Hippo pathway effectors is implicated in a wide range of cancers, including prostate, gastric and liver cancer...
March 20, 2018: Cancers
Catarina S H Jesus, Pedro Fernandes Cruz, Luis G Arnaut, Rui M M Brito, Carlos Serpa
The understanding of fast folding dynamics of single α-helices comes mostly from studies on rationally designed peptides displaying sequences with high helical propensity. The folding/unfolding dynamics and energetics of α-helix conformations in naturally occurring peptides remains largely unexplored. Here we report the study of a protein fragment analogue of the C-peptide from bovine pancreatic ribonuclease-A, RN80, a 13-amino acid residue peptide that adopts a highly populated helical conformation in aqueous solution...
March 20, 2018: Journal of Physical Chemistry. B
Judith A Smith
Protein folding in the endoplasmic reticulum (ER) is an essential cell function. To safeguard this process in the face of environmental threats and internal stressors, cells mount an evolutionarily conserved response known as the unfolded protein response (UPR). Invading pathogens induce cellular stress that impacts protein folding, thus the UPR is well situated to sense danger and contribute to immune responses. Cytokines (inflammatory cytokines and interferons) critically mediate host defense against pathogens, but when aberrantly produced, may also drive pathologic inflammation...
2018: Frontiers in Immunology
Liping Luo, Wanxiang Jiang, Hui Liu, Jicheng Bu, Ping Tang, Chongyangzi Du, Zhipeng Xu, Hairong Luo, Bilian Liu, Bo Xiao, Zhiguang Zhou, Feng Liu
The growth receptor binding protein Grb10 is an imprinted gene product and a key negative regulator of the insulin, IGF1 and mTORC1 signaling pathways. Grb10 is highly expressed in mouse fetal liver but almost completely silenced in adult mice, suggesting a potential detrimental role of this protein in adult liver function. Here we show that the grb10 gene could be reactivated in adult mouse liver by acute endoplasmic reticulum stress (ER stress) such as tunicamycin or a short-term high fat diet (HFD) challenge, concurrently with increased unfolded protein response (UPR) and hepatosteatosis...
March 19, 2018: Journal of Molecular Endocrinology
Yan Wang, Oliver Berkowitz, Jennifer Selinski, Yue Xu, Andreas Hartmann, James Whelan
In the last decade plant mitochondria have emerged as a target, sensor and initiator of signalling cascades to a variety of stress and adverse growth conditions. A combination of various 'omic profiling approaches combined with forward and reverse genetic studies have defined how mitochondria respond to stress and the signalling pathways and regulators of these responses. Reactive oxygen species (ROS)-dependent and -independent pathways, specific metabolites, complex I dysfunction, and the mitochondrial unfolded protein response (UPR) pathway have been proposed to date...
March 16, 2018: Free Radical Biology & Medicine
Satyajit Mondal, Bijan Das
The interactions of a protein cytochrome c with some selected conventional and ionic liquid surfactants have been investigated at pH7.4 using ultraviolet-visible and fluorescence spectroscopic techniques. We used four conventional surfactants - cetyltrimethylammonium bromide (CTAB), dodecyltrimethylammonium bromide (DTAB), sodium N-dodecanoylsarcosinate (SDDS), and N-decanoyl-N-methylglucamine (Mega 10), and a surface active ionic liquid 1-hexadecyl-3-methylimidazolium chloride (C16 MeImCl). All the investigated surfactants were found to induce an unfolding of the protein cytochrome c...
March 12, 2018: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
Myeongsang Lee, Hyunsung Choi, Gwonchan Yoon, Sungsoo Na
Experimental force spectroscopy has been effectively utilized for measuring structural characterization of biomolecules and mechanical properties of biomaterials. Specifically, atomic force microscopy (AFM) has been widely used to portray biomolecular characterization in single-molecule experiment by observing the unfolding behavior of the proteins. Not only the experimental techniques enable us to characterize globular protein, but computational methods like molecular dynamics (MD) also gives insight into understanding biomolecular structures...
March 12, 2018: Journal of Molecular Graphics & Modelling
Chuandong Zhu, Lixue Wang, Yang Cai, Guoxiang Wang, Hanfeng Xu, Yuan Wan, Qin Zheng
The high atomic number of gold nanoparticles (GNPs) enables them to offer potential as practical and efficient radiosensitizing agents for cancer radiotherapy applications. In the present study, it was demonstrated that GNPs can significantly modulate the irradiation response of hepatocellular carcinoma (HCC) cells in vitro and in vivo , of which the underlying mechanisms were investigated. Cetuximab (C225) is a targeting agent, which binds to the extracellular domain of epidermal growth factor receptor (EGFR)...
April 2018: Oncology Letters
Yingfeng Deng, Zhao V Wang, Ruth Gordillo, Yi Zhu, Aktar Ali, Chen Zhang, Xiaoding Wang, Mengle Shao, Zhuzhen Zhang, Puneeth Iyengar, Rana K Gupta, Jay D Horton, Joseph A Hill, Philipp E Scherer
OBJECTIVE: The spliced transcription factor Xbp1 (Xbp1s), a transducer of the unfolded protein response (UPR), regulates lipolysis. Lipolysis is stimulated by fasting when uridine synthesis is also activated in adipocytes. METHODS: Here we have examined the regulatory role Xbp1s in stimulation of uridine biosynthesis in adipocytes and triglyceride mobilization using inducible mouse models. RESULTS: Xbp1s is a key molecule involved in adipocyte uridine biosynthesis and release by activation of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD), the rate-limiting enzyme for UMP biosynthesis...
March 2, 2018: Molecular Metabolism
Camila Rubio-Patiño, Jozef P Bossowski, Gian Marco De Donatis, Laura Mondragón, Elodie Villa, Lazaro E Aira, Johanna Chiche, Rana Mhaidly, Cynthia Lebeaupin, Sandrine Marchetti, Konstantinos Voutetakis, Aristotelis Chatziioannou, Florence A Castelli, Patricia Lamourette, Emeline Chu-Van, François Fenaille, Tony Avril, Thierry Passeron, John B Patterson, Els Verhoeyen, Béatrice Bailly-Maitre, Eric Chevet, Jean-Ehrland Ricci
Dietary restriction (DR) was shown to impact on tumor growth with very variable effects depending on the cancer type. However, how DR limits cancer progression remains largely unknown. Here, we demonstrate that feeding mice a low-protein (Low PROT) isocaloric diet but not a low-carbohydrate (Low CHO) diet reduced tumor growth in three independent mouse cancer models. Surprisingly, this effect relies on anticancer immunosurveillance, as depleting CD8+ T cells, antigen-presenting cells (APCs), or using immunodeficient mice prevented the beneficial effect of the diet...
March 1, 2018: Cell Metabolism
Anthony M Mustoe, Steven Busan, Greggory M Rice, Christine E Hajdin, Brant K Peterson, Vera M Ruda, Neil Kubica, Razvan Nutiu, Jeremy L Baryza, Kevin M Weeks
mRNAs can fold into complex structures that regulate gene expression. Resolving such structures de novo has remained challenging and has limited our understanding of the prevalence and functions of mRNA structure. We use SHAPE-MaP experiments in living E. coli cells to derive quantitative, nucleotide-resolution structure models for 194 endogenous transcripts encompassing approximately 400 genes. Individual mRNAs have exceptionally diverse architectures, and most contain well-defined structures. Active translation destabilizes mRNA structure in cells...
March 13, 2018: Cell
Chen Katz, Ana Maria Low-Calle, Joshua Choe, Oleg Laptenko, David Tong, Jazmine-Saskya N Joseph-Chowdhury, Francesca Garofalo, Yan Zhu, Assaf Friedler, Carol Prives
The p53 tumor suppressor protein is the most well studied as a regulator of transcription in the nucleus, where it exists primarily as a tetramer. However, there are other oligomeric states of p53 that are relevant to its regulation and activities. In unstressed cells, p53 is normally held in check by MDM2 that targets p53 for transcriptional repression, proteasomal degradation, and cytoplasmic localization. Here we discovered a hydrophobic region within the MDM2 N-terminal domain that binds exclusively to the dimeric form of the p53 C-terminal domain in vitro...
March 16, 2018: Genes & Development
Yani Zhao, Pawel Dabrowski-Tumanski, Szymon Niewieczerzal, Joanna I Sulkowska
The folding of proteins with a complex knot is still an unresolved question. Based on representative members of Ubiquitin C-terminal Hydrolases (UCHs) that contain the 52 knot in the native state, we explain how UCHs are able to unfold and refold in vitro reversibly within the structure-based model. In particular, we identify two, topologically different folding/unfolding pathways and corroborate our results with experiment, recreating the chevron plot. We show that confinement effect of chaperonin or weak crowding greatly facilitates folding, simultaneously slowing down the unfolding process of UCHs, compared with bulk conditions...
March 16, 2018: PLoS Computational Biology
Muhammad Mosaraf Hossain, David Barua, Vahid Arabkari, Nahidul Islam, Ananya Gupta, Sanjeev Gupta
Nuclear receptor coactivators (NCOAs) function as coactivators for nuclear receptors as well as several other transcription factors and potentiate their transcriptional activity. NCOAs play an important role in biology of hormone-dependent and -independent cancers. MCB-613 is a recently described, small molecule stimulator of NCOAs and anti-neoplastic compound that leads to the death of tumour cells due to increased cellular stress. In the present study we investigated the molecular mechanism of MCB-613-induced cell death...
February 20, 2018: Oncotarget
Yi Zhang, Melanie Berghaus, Sean Klein, Kelly Jenkins, Siwen Zhang, Scott A McCallum, Joel Morgan, Roland Winter, Doug Barrick, Catherine A Royer
Many repeat proteins contain capping motifs, which serve to shield the hydrophobic core from solvent and maintain structural integrity. While the role of capping motifs in enhancing the stability and structural integrity of repeat proteins is well-documented, their contribution to folding cooperativity is not. Here we examined the role of capping motifs in defining the folding cooperativity of the leucine rich repeat protein, pp32, by monitoring the pressure and urea induced unfolding of an N-cap deletion mutant, pp32-∆N-cap, and a C-cap destabilization mutant pp32-Y131F/D146L, using residue specific NMR and SAXS...
March 12, 2018: Journal of Molecular Biology
Jianrong Li, Qilin Yu, Bing Zhang, Chenpeng Xiao, Tianyu Ma, Xiao Yi, Chao Liang, Mingchun Li
Cellular stresses could activate several response processes, such as the unfolded protein response (UPR), autophagy and oxidative stress response to restore cellular homeostasis or render cell death. Herein, we identified the Candida albicans stress-associated endoplasmic reticulum protein 1 (SERP1), also known as Ysy6, which was involved in endoplasmic reticulum (ER) stress response. We found that deletion of both SERP1/YSY6 and ATG8 led to hypersensitivity to tunicamycin (TN), and resulted in severe mitochondrial dysfunction under this stress...
March 6, 2018: International Journal of Medical Microbiology: IJMM
Sebastian Hiller, Björn M Burmann
Living cells contain molecular chaperones that are organized in intricate networks to surveil protein homeostasis by avoiding polypeptide misfolding, aggregation, and the generation of toxic species. In addition, cellular chaperones also fulfill a multitude of alternative functionalities: transport of clients towards a target location, help them fold, unfold misfolded species, resolve aggregates, or deliver clients towards proteolysis machineries. Until recently, the only available source of atomic resolution information for virtually all chaperones were crystal structures of their client-free, apo-forms...
April 2018: Journal of Magnetic Resonance
A V Finkelstein
The ability of proteins to spontaneously form their spatial structures is a long-standing puzzle in molecular biology. Experimentally measured rates of spontaneous folding of single-domain globular proteins range from microseconds to hours: the difference - 10-11 orders of magnitude - is the same as between the lifespan of a mosquito and the age of the Universe. This review (based on the literature and some personal recollections) describes a winding road to understanding spontaneous folding of protein structure...
January 2018: Biochemistry. Biokhimii︠a︡
Wenlong Zhou, Yan Yang, Liang Tang, Kai Cheng, Changkun Li, Huimin Wang, Minzhi Liu, Wei Wang
Acrolein (Acr) was used as a selection agent to improve the glutathione (GSH) overproduction of the prototrophic strain W303-1b/FGPPT . After two rounds of adaptive laboratory evolution (ALE), an unexpected result was obtained wherein identical GSH production was observed in the selected isolates. Then, a threshold selection mechanism of Acr-stressed adaption was clarified based on the formation of an Acr-GSH adduct, and a diffusion coefficient (0.36 ± 0.02 μmol·min-1 ·OD600 -1 ) was calculated. Metabolomic analysis was carried out to reveal the molecular bases that triggered GSH overproduction...
March 14, 2018: Scientific Reports
Anna Maria Fratta Pasini, Chiara Stranieri, Anna Maria Rigoni, Sergio De Marchi, Denise Peserico, Chiara Mozzini, Luciano Cominacini, Ulisse Garbin
AIM: Ischemia-reperfusion (I-R) produces reactive oxygen species (ROS) that damage cells and favour cytotoxicity and apoptosis in peripheral artery disease (PAD) patients. Since brief episodes of I-R (ischemic conditioning) protect cells against ischemic harms, we evaluated whether a short-course of supervised treadmill training, characterized by repeated episodes of I-R, makes peripheral blood mononuclear cells (PBMCs) from PAD patients with intermittent claudication more resistant to I-R injuries by reducing oxidative stress and by inducing an adaptative response of unfolded protein response (UPR) and nuclear factor-E2-related factor (Nrf2) pathway expression...
March 13, 2018: Journal of Atherosclerosis and Thrombosis
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