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Lance R English, Erin C Tilton, Benjamin J Ricard, Steven T Whitten
Proteins that lack tertiary stability under normal conditions, known as intrinsically disordered, exhibit a wide range of biological activities. Molecular descriptions for the biology of intrinsically disordered proteins (IDPs) consequently rely on disordered structural models, which in turn require experiments that assess the origins to structural features observed. For example, while hydrodynamic size is mostly insensitive to sequence composition in chemically denatured proteins, IDPs show strong sequence-specific effects in the hydrodynamic radius (Rh ) when measured under normal conditions...
December 9, 2016: Proteins
Anne Müller, Julia Catherine Berkmann, Patrick Scheerer, Heike Biebermann, Gunnar Kleinau
The murine G-protein coupled receptor 83 (mGPR83) is expressed in the hypothalamus and was previously suggested to be involved in the regulation of metabolism. The neuropeptide PEN has been recently identified as a potent GPR83 ligand. Moreover, GPR83 constitutes functionally relevant hetero-oligomers with other G-protein coupled receptors (GPCR) such as the ghrelin receptor (GHSR) or GPR171. Previous deletion studies also revealed that the long N-terminal extracellular receptor domain (eNDo) of mGPR83 may act as an intra-molecular ligand, which participates in the regulation of basal signaling activity, which is a key feature of GPCR function...
2016: PloS One
Alexandra Balaceanu, Marco Pasi, Pablo D Dans, Adam Hospital, Richard Lavery, Modesto Orozco
An accurate understanding of DNA backbone transitions is likely to be the key for elucidating the puzzle of the intricate sequence-dependent mechanical properties that govern most of the biologically relevant functions of the double helix. One factor believed to be important in indirect recognition within protein-DNA complexes is the combined effect of two DNA backbone torsions (ε and ζ) which give rise to the well-known BI/BII conformational equilibrium. In this work we explain the sequence-dependent BII propensity observed in RpY steps (R = purine; Y = pyrimidine) at the tetranucleotide level with the help of a previously undetected C-H···O contact between atoms belonging to adjacent bases...
December 9, 2016: Journal of Physical Chemistry Letters
Zhiwei Liu, Xiaobo Hu, Ara M Abramyan, Ádám Mészáros, Marton Csekei, András Kotschy, Ivan Huc, Vojislava Pophristic
Metadynamics simulations were used to describe the conformational energy landscapes of several helically folded aromatic quinolinecarboxamide oligomers bearing a single chiral group at either the C- or N-terminus. The calculations allowed prediction of whether a helix handedness bias occurs under the influence of the chiral group and gave insight into the interactions - sterics, electrostatics, hydrogen bonds - responsible for a particular helix sense preference. In the case of camphanyl-based and morpholine-based chiral groups, experimental data confirming the validity of the calculations had already been available...
December 9, 2016: Chemistry: a European Journal
Sha Gong, Yujie Wang, Zhen Wang, Yanli Wang, Wenbing Zhang
Riboswitches are self-regulatory elements located at the 5' untranslated region of certain mRNAs. The Enterococcus faecalis SAM-III (SMK) riboswitch regulates downstream gene expression through conformational change by sensing S-adenosylmethionine (SAM) at the translation level. Using the recently developed systematic helix-based computational method, we studied the co-transcriptional folding behavior of the SMK riboswitch and its shortened construct lacking the first six nucleotides. We find that there are no obvious misfolded structures formed during the transcription and refolding processes for this riboswitch...
December 8, 2016: Journal of Physical Chemistry. B
Alessandra Del Giudice, Cedric Dicko, Luciano Galantini, Nicolae V Pavel
The most abundant plasma protein, human serum albumin (HSA), plays a key part in the body's antioxidant defense against reactive species. This study was aimed at correlating oxidant-induced chemical and structural effects on HSA. Despite the chemical modification induced by the oxidant hypochlorite, the native shape is preserved up to oxidant/HSA molar ratio <80, above which a structural transition occurs in the critical range 80-120. This conformational variation involves the drifting of one of the end-domains from the rest of the protein and corresponds to the loss of one-third of the α-helix and a net increase of the protein negative charge...
December 8, 2016: Journal of Physical Chemistry. B
Lishan Liu, John Hess, Indra D Sahu, Paul G FitzGerald, Robert M McCarrick, Gary A Lorigan
Previously, an electron spin echo envelope modulation (ESEEM) spectroscopic approach was established to probe the local secondary structure of membrane proteins and peptides utilizing site-directed spin-labeling (SDSL). In this method, the side chain of one amino acid residue is selectively (2)H-labeled and a nitroxide spin label is strategically placed 1, 2, 3, or 4 amino acids away from the (2)H-labeled amino acid (denoted as i ± 1 to i ± 4, i represents the (2)H-labeled amino acid). ESEEM can detect the dipolar coupling between the nitroxide spin label and (2)H atoms on the amino acid side chain...
December 8, 2016: Journal of Physical Chemistry. B
Theodore J Zwang, Sylvia Hürlimann, Michael G Hill, Jacqueline K Barton
Recent work suggests that electrons can travel through DNA and other chiral molecules in a spin-selective manner, but little is known about the origin of this spin selectivity. Here we describe experiments on magnetized DNA-modified electrodes to explore spin-selective electron transport through hydrated duplex DNA. Our results show that the two spins migrate through duplex DNA with a different yield and that spin selectivity requires charge transport through the DNA duplex. Significantly, shifting the same duplex DNA between right-handed B- and left-handed Z-forms leads to a diode-like switch in spin selectivity; which spin moves more efficiently through the duplex depends upon the DNA helicity...
December 7, 2016: Journal of the American Chemical Society
Yuan Zhang, Christopher Roland, Celeste Sagui
A (GGGGCC) hexanucleotide repeat (HR) expansion in the C9ORF72 gene, and its associated antisense (CCCCGG) expansion, are considered the major cause behind frontotemporal dementia and amyotrophic lateral sclerosis. We have performed molecular dynamics simulations to characterize the conformation and dynamics of the twelve duplexes that result from the three different reading frames in sense and antisense HRs for both DNA and RNA. These duplexes display atypical structures relevant not only for a molecular level understanding of these diseases but also for enlarging the repertoire of nucleic-acid structural motifs...
December 9, 2016: ACS Chemical Neuroscience
Shaweta Gupta, Srirupa Chakraborty, Ridhima Vij, Anthony Auerbach
Nicotinic acetylcholine receptors are allosteric proteins that generate membrane currents by isomerizing ("gating") between resting and active conformations under the influence of neurotransmitters. Here, to explore the mechanisms that link the transmitter-binding sites (TBSs) with the distant gate, we use mutant cycle analyses to measure coupling between residue pairs, phi value analyses to sequence domain rearrangements, and current simulations to reproduce a microsecond shut component ("flip") apparent in single-channel recordings...
December 8, 2016: Journal of General Physiology
Aviram Rasouly, Bibhusita Pani, Evgeny Nudler
Nucleotide excision repair (NER) is the key DNA repair system that eliminates the majority of DNA helix-distorting lesions. RNA polymerase (RNAP) expedites the recognition of DNA damage by NER components via transcription-coupled DNA repair (TCR). In bacteria, a modified nucleotide ppGpp ('magic spot') is a pleiotropic second messenger that mediates the response to nutrient deficiencies by altering the initiation properties of RNAP. In this review, we discuss newly elucidated roles of guanosine 5'-diphosphate 3'-diphosphate (ppGpp) in transcription elongation that couple this alarmone to DNA damage repair and maintenance...
December 5, 2016: Trends in Genetics: TIG
Wei Huang, Prashant S Emani, Gabriele Varani, Gary P Drobny
Intrinsic motions may allow HIV-1 TAR RNA to change its conformation to form a functional complex with the Tat protein, which is essential for viral replication. Understanding the dynamic properties of TAR necessitates determining motion on the intermediate ns-μs time scale. To this end, we performed solid-state deuterium NMR line shape and T1Z relaxation time experiments to measure intermediate motions for two uridine residues, U40 and U42, within the lower helix of TAR. We infer global motions at rates of ~10(5) s(-1) in the lower helix, which are much slower than those of the upper helix (~10(6) s(-1)), indicating the two helical domains reorient independently of one another in the solid-state sample...
December 8, 2016: Journal of Physical Chemistry. B
Ting-Chih Yeh, Tzu-Ting Huang, Tien-Shun Yeh, Yu-Ren Chen, Kai-Wen Hsu, Pen-Hui Yin, Hsin-Chen Lee, Ling-Ming Tseng
TWIST1 is a highly conserved basic helix-loop-helix transcription factor that contributes to cancer metastasis by promoting an epithelial-mesenchymal transition and repressing E-cadherin gene expression in breast cancer. In this study, we explored the potential role of miR-151 in TWIST1 expression and cancer properties in human breast cancer cells. We found that the human TWIST1 3'UTR contains a potential binging site for miR-151-3p at the putative target sequence 5'-CAGUCUAG-3'. Using a TWIST1-3'UTR luciferase reporter assay, we demonstrated that the target sequence within the TWIST1 3'UTR is required for miR-151-3p regulation of TWIST1 expression...
2016: PloS One
Amit D Gujar, Son Le, Diane D Mao, David Y A Dadey, Alice Turski, Yo Sasaki, Diane Aum, Jingqin Luo, Sonika Dahiya, Liya Yuan, Keith M Rich, Jeffrey Milbrandt, Dennis E Hallahan, Hiroko Yano, David D Tran, Albert H Kim
Accumulating evidence suggests cancer cells exhibit a dependency on metabolic pathways regulated by nicotinamide adenine dinucleotide (NAD(+)). Nevertheless, how the regulation of this metabolic cofactor interfaces with signal transduction networks remains poorly understood in glioblastoma. Here, we report nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD(+) synthesis, is highly expressed in glioblastoma tumors and patient-derived glioblastoma stem-like cells (GSCs). High NAMPT expression in tumors correlates with decreased patient survival...
December 7, 2016: Proceedings of the National Academy of Sciences of the United States of America
Shalaka Chitale, Holger Richly
Damaged DNA is repaired by specialized repair factors that are recruited in a well-orchestrated manner to the damage site. The DNA damage response at UV inflicted DNA lesions is accompanied by posttranslational modifications of DNA repair factors and the chromatin environment sourrounding the lesion. In particular, mono- and poly-ubiquitylation events are an integral part of the DNA damage signalling. Whereas ubiquitin signalling at DNA doublestrand breaks has been subject to intensive studies comparatively little is known about the intricacies of ubiquitylation events occuring during nucleotide excision repair (NER), the major pathway to remove bulky helix lesions...
December 8, 2016: Cell Cycle
Simon Mysling, Kristian Kølby Kristensen, Mikael Larsson, Oleg Kovrov, André Bensadouen, Thomas Jd Jørgensen, Gunilla Olivecrona, Stephen G Young, Michael Ploug
Lipoprotein lipase (LPL) undergoes spontaneous inactivation via global unfolding and this unfolding is prevented by GPIHBP1 (Mysling et al., 2016). We now show: (1) that ANGPTL4 inactivates LPL by catalyzing the unfolding of its hydrolase domain; (2) that binding to GPIHBP1 renders LPL largely refractory to this inhibition; and (3) that both the LU domain and the intrinsically disordered acidic domain of GPIHBP1 are required for this protective effect. Genetic studies have found that a common polymorphic variant in ANGPTL4 results in lower plasma triglyceride levels...
December 8, 2016: ELife
Yandong Zhou, Xiangyu Cai, Natalia A Loktionova, Xianming Wang, Robert M Nwokonko, Xizhuo Wang, Youjun Wang, Brad S Rothberg, Mohamed Trebak, Donald L Gill
The ubiquitously expressed Orai Ca(2+) channels are gated through a unique process of intermembrane coupling with the Ca(2+)-sensing STIM proteins. Despite the significance of Orai1-mediated Ca(2+) signals, how gating of Orai1 is triggered by STIM1 remains unknown. A widely held gating model invokes STIM1 binding directly to Orai1 pore-forming helix. Here we report that an Orai1 C-terminal STIM1-binding site, situated far from the N-terminal pore helix, alone provides the trigger that is necessary and sufficient for channel gating...
December 8, 2016: Nature Communications
Oriol Marimon, João M C Teixeira, Tiago N Cordeiro, Valerie W C Soo, Thammajun L Wood, Maxim Mayzel, Irene Amata, Jesús García, Ainara Morera, Marina Gay, Marta Vilaseca, Vladislav Yu Orekhov, Thomas K Wood, Miquel Pons
The Hha and TomB proteins from Escherichia coli form an oxygen-dependent toxin-antitoxin (TA) system. Here we show that YmoB, the Yersinia orthologue of TomB, and its single cysteine variant [C117S]YmoB can replace TomB as antitoxins in E. coli. In contrast to other TA systems, [C117S]YmoB transiently interacts with Hha (rather than forming a stable complex) and enhances the spontaneous oxidation of the Hha conserved cysteine residue to a -SOxH-containing species (sulfenic, sulfinic or sulfonic acid), which destabilizes the toxin...
December 8, 2016: Nature Communications
Insung Na, Shelly DeForte, Bosko M Stojanovski, Gloria C Ferreira, Vladimir N Uversky
Heme biosynthesis, a complex, multistage, and tightly controlled process, starts with 5-aminolevulinate (ALA) production, which, in metazoa and certain bacteria, is a reaction catalyzed by 5-aminolevulinate synthase (ALAS), a pyridoxal 5'-phosphate (PLP)-dependent enzyme. Functional aberrations in ALAS are associated with several human diseases. ALAS can adopt open and closed conformations, with segmental rearrangements of a C-terminal, 16-amino acid loop and an α-helix regulating accessibility to the ALAS active site...
December 8, 2016: Journal of Biomolecular Structure & Dynamics
Vivek Hamse Kameshwar, Kumar J R, Babu S Priya, S Nanjunda Swamy
Secretory phospholipase A2 (sPLA2) is a key enzyme participating in the inflammatory cascade followed by the action of cyclooxygenase-2 and lipoxygenases. Therefore, inhibitors of sPLA2 could be used as potent anti-inflammatory agents to treat the early phase of inflammation. In this study, we have prepared the fenoprofen and ibuprofen analogs containing 1,3,4-oxadiazole nucleus and tested against Vipera russelli venom's basic sPLA2 (VRV-PL-VIIIa). Among the tested ligands 5(a-t),2-(2-chlorophenyl)-5-(1-(4-phenoxyphenyl) ethyl)-1,3,4-oxadiazole (5m) inhibited the catalytic activity of VRV-PL-VIIIa with an IC50 value of 11...
December 7, 2016: Molecular and Cellular Biochemistry
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