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Longcan Mei, Yanping Zhou, Lizhe Zhu, Changlin Liu, Zhuo Wu, Fangkui Wang, Gefei Hao, Di Yu, Hong Yuan, Yanfang Cui
A superkine variant of interleukin-2 with six site mutations away from the binding interface developed from the yeast display technique has been previously characterized as undergoing a distal structure alteration which is responsible for its super-potency and provides an elegant case study with which to get insight about how to utilize allosteric effect to achieve desirable protein functions. By examining the dynamic network and the allosteric pathways related to those mutated residues using various computational approaches, we found that nanosecond time scale all-atom molecular dynamics simulations can identify the dynamic network as efficient as an ensemble algorithm...
March 20, 2018: International Journal of Molecular Sciences
Michaela Lichtenegger, Oleksandra Tiapko, Barbora Svobodova, Thomas Stockner, Toma N Glasnov, Wolfgang Schreibmayer, Dieter Platzer, Gema Guedes de la Cruz, Sarah Krenn, Romana Schober, Niroj Shrestha, Rainer Schindl, Christoph Romanin, Klaus Groschner
Transient receptor potential canonical (TRPC) channels TRPC3, TRPC6 and TRPC7 are able to sense the lipid messenger diacylglycerol (DAG). The DAG-sensing and lipid-gating processes in these ion channels are still unknown. To gain insights into the lipid-sensing principle, we generated a DAG photoswitch, OptoDArG, that enabled efficient control of TRPC3 by light. A structure-guided mutagenesis screen of the TRPC3 pore domain unveiled a single glycine residue behind the selectivity filter (G652) that is exposed to lipid through a subunit-joining fenestration...
March 19, 2018: Nature Chemical Biology
Arunkumar Krishnan, Lakshminarayan M Iyer, Stephen J Holland, Thomas Boehm, L Aravind
AID/APOBEC deaminases (AADs) convert cytidine to uridine in single-stranded nucleic acids. They are involved in numerous mutagenic processes, including those underpinning vertebrate innate and adaptive immunity. Using a multipronged sequence analysis strategy, we uncover several AADs across metazoa, dictyosteliida, and algae, including multiple previously unreported vertebrate clades, and versions from urochordates, nematodes, echinoderms, arthropods, lophotrochozoans, cnidarians, and porifera. Evolutionary analysis suggests a fundamental division of AADs early in metazoan evolution into secreted deaminases (SNADs) and classical AADs, followed by diversification into several clades driven by rapid-sequence evolution, gene loss, lineage-specific expansions, and lateral transfer to various algae...
March 19, 2018: Proceedings of the National Academy of Sciences of the United States of America
Xuanyan Jia, Jianyun Yao, Zengqiang Gao, Guangfeng Liu, Yuhui Dong, Xiaoxue Wang, Heng Zhang
Toxin-antitoxin (TA) loci in bacteria are small genetic modules that regulate various cellular activities, including cell growth and death. The two-gene module encoding a HEPN (higher eukaryotes and prokaryotes nucleotide-binding) domain and a cognate MNT (minimal nucleotidyltransferase) domain has been predicted to represent a novel type II TA system prevalent in archaea and bacteria. However, the neutralization mechanism and cellular targets of the TA family remain unclear. The toxin SO_3166 having a HEPN domain and its cognate antitoxin SO_3165 with an MNT domain constitute a typical type II TA system that regulates cell motility and confers plasmid stability in the bacterium Shewanella oneidensis...
March 19, 2018: Journal of Biological Chemistry
Hannah Klaassen, Yongfu Wang, Kay Adamski, Nicolas Rohner, Johanna E Kowalko
Understanding the genetic basis of trait evolution is critical to identifying the mechanisms that generated the immense amount of diversity observable in the living world. However, genetically manipulating organisms from natural populations with evolutionary adaptations remains a significant challenge. Astyanax mexicanus, the blind Mexican cavefish, exists in two interfertile forms, a surface-dwelling form and multiple independently evolved cave-dwelling forms. Cavefish have evolved a number of morphological and behavioral traits and multiple quantitative trait loci (QTL) analyses have been performed to identify loci underlying these traits...
March 16, 2018: Developmental Biology
Haofeng Gao, Chanjuan Li, Ramesh Bandikari, Ziduo Liu, Nan Hu, Qiang Yong
BACKGROUND: In industries lipolytic reactions occur in insensitive conditions such as high temperature thus novel stout esterases with unique properties are attracts to the industrial application. Protein engineering is the tool to obtain desirable characters of enzymes. A novel esterase gene was isolated from South China Sea and subjected to a random mutagenesis and site directed mutagenesis for higher activity and thermo-stability compared to wild type. RESULTS: A novel esterase showed the highest hydrolytic activity against p-nitrophenyl acetate (pNPA, C2) and the optimal activity at 40 °C and pH 8...
March 19, 2018: Microbial Cell Factories
Yihui Zhai, Hong Xu, Qian Shen, Franz Schaefer, Claus P Schmitt, Jing Chen, Haimei Liu, Jialu Liu, Jiaojiao Liu
BACKGROUND: Bicarbonate-based peritoneal dialysis (PD) fluids enhance the migratory capacity and damage-repair ability of human peritoneal mesothelial cells by upregulating AQP1. However, little is known about the underlying molecular mechanisms. RESULTS: Here we used HEK-293T cells to investigate the effect of pH on AQP1 gene transcription levels. We found that AQP1 mRNA levels increases with pH. Transfection of HEK-293T cells with luciferase reporter vectors containing different regions of the AQP1 promoter identified an upstream region in the AQP1 gene between - 2200 and - 2300 bp as an enhancer required for pH-mediated regulation of AQP1 expression...
March 20, 2018: BMC Molecular Biology
Ayako Yamanishi, Atsushi Matsuba, Ryohei Kondo, Rie Akamatsu, Sachiyo Tanaka, Masahiro Tokunaga, Kyoji Horie, Chikara Kokubu, Yasumasa Ishida, Junji Takeda
Haploid mouse embryonic stem cells (ESCs), in which a single hit mutation is sufficient to produce loss-of-function phenotypes, have provided a powerful tool for forward genetic screening. This strategy, however, can be hampered by undesired autodiploidization of haploid ESCs. To overcome this obstacle, we designed a new methodology that facilitates enrichment of homozygous mutant ESC clones arising from autodiploidization during haploid gene trap mutagenesis. Haploid mouse ESCs were purified by fluorescence-activated cell sorting to maintain their haploid property and then transfected with the Tol2 transposon-based biallelically polyA-trapping (BPATrap) vector that carries an invertible G418 plus puromycin double selection cassette...
March 15, 2018: Nucleic Acids Research
Zheng Cui, Xiachang Wang, Stefan Koppermann, Jon S Thorson, Christian Ducho, Steven G Van Lanen
Muraymycins are nucleoside antibiotics isolated from Streptomyces sp. NRRL 30471 and several mutant strains thereof that were generated by random, chemical mutagenesis. Reinvestigation of two mutant strains using new media conditions led to the isolation of three new muraymycin congeners, named B8, B9, and C6 (1-3), as well as a known muraymycin, C1. Structures of the compounds were elucidated by HRMS and 1D and 2D NMR spectroscopic analyses. Complete 2D NMR assignments for the known muraymycin C1 are also provided for the first time...
March 19, 2018: Journal of Natural Products
Ava Yuan Xue, Antonella Di Pizio, Anat Levit, Tali Yarnitzky, Osnat Penn, Tal Pupko, Masha Y Niv
The 25 human bitter taste receptors (hT2Rs) recognize thousands of structurally and chemically diverse bitter substances. The binding modes of human bitter taste receptors hT2R10 and hT2R46, which are responsible for strychnine recognition, were previously established using site-directed mutagenesis, functional assays, and molecular modeling. Here we construct a phylogenetic tree and reconstruct ancestral sequences of the T2R10 and T2R46 clades. We next analyze the binding sites in view of experimental data to predict their ability to recognize strychnine...
2018: Frontiers in Molecular Biosciences
Andrew S Fister, Lena Landherr, Siela N Maximova, Mark J Guiltinan
Theobroma cacao , the source of cocoa, suffers significant losses to a variety of pathogens resulting in reduced incomes for millions of farmers in developing countries. Development of disease resistant cacao varieties is an essential strategy to combat this threat, but is limited by sources of genetic resistance and the slow generation time of this tropical tree crop. In this study, we present the first application of genome editing technology in cacao, using Agrobacterium-mediated transient transformation to introduce CRISPR/Cas9 components into cacao leaves and cotyledon cells...
2018: Frontiers in Plant Science
Mei-Yi Lu, Syuan-Shao Lu, Shiann-Luen Chang, Fang Liao
CCR6 is a G protein-coupled receptor (GPCR) that recognizes a single chemokine ligand, CCL20 and is primarily expressed by leukocytes. Upon ligand binding, CCR6 activates Gαi heterotrimeric G proteins to induce various potential cellular outcomes through context-specific cell signaling. It is well known that differential phosphorylation of Ser and Thr residues in the C-terminal domains or intracellular loops of GPCRs can generate barcodes that regulate GPCR function by regulating the recruitment of β-arrestins...
2018: Frontiers in Immunology
Marco A Alfonzo-Méndez, Gabriel Carmona-Rosas, David A Hernández-Espinosa, M Teresa Romero-Ávila, J Adolfo García-Sáinz
Human α1D -adrenoceptors (α1D -ARs) are a group of the seven transmembrane-spanning proteins that mediate many of the physiological and pathophysiological actions of adrenaline and noradrenaline. Although it is known that α1D -ARs are phosphoproteins, their specific phosphorylation sites and the kinases involved in their phosphorylation remain largely unknown. Using a combination of in silico analysis, mass spectrometry and site directed mutagenesis, we identified distinct α1D -AR phosphorylation patterns during noradrenaline- or phorbol ester-mediated desensitizations...
March 15, 2018: Biochimica et Biophysica Acta
Bita Zamiri, Mila Mirceta, Rashid Abu-Ghazalah, Marc S Wold, Christopher E Pearson, Robert B Macgregor
BACKGROUND: Expansion of the C9orf72 hexanucleotide repeat (GGGGCC)n •(GGCCCC)n is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both strands of the C9orf72 repeat have been shown to form unusual DNA and RNA structures that are thought to be involved in mutagenesis and/or pathogenesis. We previously showed that the C-rich DNA strands from the C9orf72 repeat can form four-stranded quadruplexes at neutral pH. The cytosine residues become protonated under slightly acidic pH (pH 4...
March 14, 2018: Biochimica et Biophysica Acta
Qi Gao, Chao Lu, Xiao-Wen Wang, Jun-Wei Zhang, Youtao Song, You-Lin Xue
Irisin is found closely associated with promoting the browning of beige fat cells in white adipose tissue. The crystal structure reveals that irisin forms a continuous inter-subunit β-sheet dimer. Here, molecular dynamics (MD) simulation and steered molecular dynamics (SMD) simulation were performed to investigate the dissociation process and the intricate interactions between the two irisin monomers. In the process of MD, the interactions between the monomers were roughly analyzed through the average numbers of both hydrophobic contacts and H-bonds...
March 16, 2018: Journal of Molecular Modeling
Takahiro Sawada, Miho Eguchi, Seiya Asaki, Ryota Kashiwagi, Kousuke Shimomura, Fumiko Taguchi, Hidenori Matsui, Mikihiro Yamamoto, Yoshiteru Noutoshi, Kazuhiro Toyoda, Yuki Ichinose
Our previous studies revealed that flagellar-motility-defective mutants such as ∆fliC of Pseudomonas syringae pv. tabaci 6605 (Pta6605) have remarkably reduced production of N-acyl-homoserine lactones (AHL), quorum-sensing molecules. To investigate the reason of loss of AHL production in ∆fliC mutant, we carried out transposon mutagenesis. Among approximately 14,000 transconjugants, we found 11 AHL production-recovered (APR) strains. In these APR strains, a transposon was inserted into either mexE or mexF, genes encoding for the multidrug efflux pump transporter MexEF-OprN, and mexT, a gene encoding a putative transcriptional activator for mexEF-oprN...
March 16, 2018: Molecular Genetics and Genomics: MGG
Benedikt Wynands, Christoph Lenzen, Maike Otto, Falk Koch, Lars M Blank, Nick Wierckx
Aromatic chemicals are important building blocks for the production of a multitude of everyday commodities. Currently, aromatics production relies almost exclusively on petrochemical processes. To achieve sustainability, alternative synthesis methods need to be developed. Here, we strived for an efficient production of phenol, a model aromatic compound of industrial relevance, from renewable carbon sources using the solvent-tolerant biocatalyst Pseudomonas taiwanensis VLB120. First, multiple catabolic routes for the degradation of aromatics and related compounds were inactivated, thereby obtaining the chassis strain P...
March 13, 2018: Metabolic Engineering
Moumita Datta, Ori Staszewski, Elena Raschi, Maximilian Frosch, Nora Hagemeyer, Tuan Leng Tay, Thomas Blank, Mario Kreutzfeldt, Doron Merkler, Stephanie Ziegler-Waldkirch, Patrick Matthias, Melanie Meyer-Luehmann, Marco Prinz
Microglia as tissue macrophages contribute to the defense and maintenance of central nervous system (CNS) homeostasis. Little is known about the epigenetic signals controlling microglia function in vivo. We employed constitutive and inducible mutagenesis in microglia to delete two class I histone deacetylases, Hdac1 and Hdac2. Prenatal ablation of Hdac1 and Hdac2 impaired microglial development. Mechanistically, the promoters of pro-apoptotic and cell cycle genes were hyperacetylated in absence of Hdac1 and Hdac2, leading to increased apoptosis and reduced survival...
March 7, 2018: Immunity
María Victoria Repetto, Matthew J Winters, Alan Bush, Wolfgang Reiter, David Maria Hollenstein, Gustav Ammerer, Peter M Pryciak, Alejandro Colman-Lerner
We report an unanticipated system of joint regulation by cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK), involving collaborative multi-site phosphorylation of a single substrate. In budding yeast, the protein Ste5 controls signaling through a G1 arrest pathway. Upon cell-cycle entry, CDK inhibits Ste5 via multiple phosphorylation sites, disrupting its membrane association. Using quantitative time-lapse microscopy, we examined Ste5 membrane recruitment dynamics at different cell-cycle stages...
March 15, 2018: Molecular Cell
Vladimir Anatolievich Chistyakov, Evgeniya Valer'evna Prazdnova, Maria Sergeevna Mazanko, Anzhelica Borisovna Bren
A model system based on the Escherichia coli MG1655 (pRecA-lux) Lux-biosensor was used to evaluate the ability of the fermentates of eight probiotic strains to reduce the SOS response stimulated by ciprofloxacin in bacteria and mutagenesis mediated by it. Preliminary attempts to estimate the chemical nature of active components of the fermentates were conducted.
March 16, 2018: Biosensors
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