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Site directed mutations

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https://www.readbyqxmd.com/read/28107644/synergism-of-dam-muth-and-muts-in-methylation-directed-mismatch-repair-in-escherichia-coli
#1
Changkun Hu, Yunqi Zhao, Huiyun Sun, Yixin Yang
DNA mismatch repair (MMR) is a critical mutation surveillance system for recognizing and repairing erroneous insertion, deletion, and disincorporation of base. Major components of mismatch repair system consist of MutH, MutL, and MutS. Dam methylates adenine to distinguish newly synthesized daughter strands from the parent strands. Employing a tyrosine-auxotrophic E. coli FX-11 strain, the mutation frequency can be determined by the number of tyrosine revertants and the cell viability of FX-11 with deficiencies in dam and mismatch repair proteins...
January 6, 2017: Mutation Research
https://www.readbyqxmd.com/read/28105914/homology-modeling-and-molecular-dynamics-provide-structural-insights-into-tospovirus-nucleoprotein
#2
Rayane Nunes Lima, Muhammad Faheem, João Alexandre Ribeiro Gonçalves Barbosa, Marcelo Depólo Polêto, Hugo Verli, Fernando Lucas Melo, Renato Oliveira Resende
BACKGROUND: Tospovirus is a plant-infecting genus within the family Bunyaviridae, which also includes four animal-infecting genera: Hantavirus, Nairovirus, Phlebovirus and Orthobunyavirus. Compared to these members, the structures of Tospovirus proteins still are poorly understood. Despite multiple studies have attempted to identify candidate N protein regions involved in RNA binding and protein multimerization for tospovirus using yeast two-hybrid systems (Y2HS) and site-directed mutagenesis, the tospovirus ribonucleocapsids (RNPs) remains largely uncharacterized at the molecular level and the lack of structural information prevents detailed insight into these interactions...
December 15, 2016: BMC Bioinformatics
https://www.readbyqxmd.com/read/28105535/the-neuropeptide-orexin-a-inhibits-the-gabaa-receptor-by-pkc-and-ca-2-camkii-dependent-phosphorylation-of-its-%C3%AE-1-subunit
#3
Divya Sachidanandan, Haritha P Reddy, Anitha Mani, Geoffrey J Hyde, Amal Kanti Bera
Orexin-A and orexin-B (Ox-A, Ox-B) are neuropeptides produced by a small number of neurons that originate in the hypothalamus and project widely in the brain. Only discovered in 1998, the orexins are already known to regulate several behaviours. Most prominently, they help to stabilise the waking state, a role with demonstrated significance in the clinical management of narcolepsy and insomnia. Orexins bind to G-protein-coupled receptors (predominantly postsynaptic) of two subtypes, OX1R and OX2R. The primary effect of Ox-OXR binding is a direct depolarising influence mediated by cell membrane cation channels, but a wide variety of secondary effects, both pre- and postsynaptic, are also emerging...
January 19, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28103689/structure-and-function-of-a-c-c-bond-cleaving-oxygenase-in-atypical-angucycline-biosynthesis
#4
Guohui Pan, Xiaoqin Gao, Keqiang Fan, Junlin Liu, Bing Meng, Jinmin Gao, Bin Wang, Chaobo Zhang, Hui Han, Guomin Ai, Yihua Chen, Dong Wu, Zhi-Jie Liu, Keqian Yang
C-C bond ring cleaving oxygenases represent a unique family of enzymes involved in the B ring cleavage reaction only observed in atypical angucycline biosynthesis. B ring cleavage is the key reaction leading to dramatic divergence in the final structures of atypical angucyclines. Here, we present the crystal structure of AlpJ, the first structure of this family of enzymes. AlpJ has been verified as the enzyme catalyzing C-C bond cleavage in kinamycin biosynthesis. The crystal structure of the AlpJ monomer resembles the dimeric structure of ferredoxin-like proteins...
January 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28103677/inversion-of-extender-unit-selectivity-in-the-erythromycin-polyketide-synthase-by-acyltransferase-domain-engineering
#5
Irina Koryakina, Christian Kasey, John B McArthur, Andrew N Lowell, Joseph A Chemler, Shasha Li, Douglas A Hansen, David H Sherman, Gavin J Williams
Acyltransferase (AT) domains of polyketide synthases (PKSs) select extender units for incorporation into polyketides and dictate large portions of the structures of clinically relevant natural products. Accordingly, there is significant interest in engineering the substrate specificity of PKS ATs in order to site-selectively manipulate polyketide structure. However, previous attempts to engineer ATs have yielded mutant PKSs with relaxed extender unit specificity, rather than an inversion of selectivity from one substrate to another...
January 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28103251/active-hydrogen-bond-network-ahbn-and-applications-for-improvement-of-thermal-stability-and-ph-sensitivity-of-pullulanase-from-bacillus-naganoensis
#6
Qing-Yan Wang, Neng-Zhong Xie, Qi-Shi Du, Yan Qin, Jian-Xiu Li, Jian-Zong Meng, Ri-Bo Huang
A method, so called "active hydrogen bond network" (AHBN), is proposed for site-directed mutations of hydrolytic enzymes. In an enzyme the AHBN consists of the active residues, functional residues, and conservative water molecules, which are connected by hydrogen bonds, forming a three dimensional network. In the catalysis hydrolytic reactions of hydrolytic enzymes AHBN is responsible for the transportation of protons and water molecules, and maintaining the active and dynamic structures of enzymes. The AHBN of pullulanase BNPulA324 from Bacillus naganoensis was constructed based on a homologous model structure using Swiss Model Protein-modeling Server according to the template structure of pullulanase BAPulA (2WAN)...
2017: PloS One
https://www.readbyqxmd.com/read/28102315/methyl-cytosine-driven-structural-changes-enhance-adduction-kinetics-of-an-exon-7-fragment-of-the-p53-gene
#7
Spundana Malla, Karteek Kadimisetty, You-Jun Fu, Dharamainder Choudhary, John B Schenkman, James F Rusling
Methylation of cytosine (C) at C-phosphate-guanine (CpG) sites enhances reactivity of DNA towards electrophiles. Mutations at CpG sites on the p53 tumor suppressor gene that can result from these adductions are in turn correlated with specific cancers. Here we describe the first restriction-enzyme-assisted LC-MS/MS sequencing study of the influence of methyl cytosines (MeC) on kinetics of p53 gene adduction by model metabolite benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), using methodology applicable to correlate gene damage sites for drug and pollutant metabolites with mutation sites...
January 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28100785/protein-kinase-c-controls-binding-of-igo-ensa-proteins-to-protein-phosphatase-2a-in-budding-yeast
#8
Vu Thai, Noah Dephoure, Amit Weiss, Jacqueline Ferguson, Ricardo Leitao, Steven P Gygi, Douglas R Kellogg
Protein phosphatase 2A (PP2A) plays important roles in controlling mitosis in all eukaryotic cells. The form of PP2A that controls mitosis is associated with a conserved regulatory subunit that is called B55 in vertebrates and Cdc55 in budding yeast. The activity of this form of PP2A can be inhibited by binding of conserved Igo/ENSA proteins. Although the mechanisms that activate Igo/ENSA to bind to PP2A are well understood, little is known about how they are inactivated. Here, we have analyzed regulation of Igo/ENSA in the context of a checkpoint pathway that links mitotic entry to membrane growth in budding yeast...
January 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28100305/environment-directed-activation-the-escherichia-coli-flhdc-operon-by-transposons
#9
Zhongge Zhang, Chika Kukita, Mir Zafri Humayun, Milton H Saier
The flagellar system in E. coli K12 is expressed under the control of the flhDC-encoded master regulator, FlhDC. Transposition of insertion sequence (IS) elements to the upstream flhDC promoter region up-regulates transcription of this operon, resulting in more rapid motility. Wang and Wood (2011) provided evidence that insertion of IS5 into upstream activating sites occurs at higher rates in semisolid agar media in which swarming behavior is allowed as compared with liquid or solid media where swarming cannot occur...
January 17, 2017: Microbiology
https://www.readbyqxmd.com/read/28096902/functional-characterization-of-the-active-mutator-like-transposable-element-muta1-from-the-mosquito-aedes-aegypti
#10
Kun Liu, Susan R Wessler
BACKGROUND: Mutator-like transposable elements (MULEs) are widespread with members in fungi, plants, and animals. Most of the research on the MULE superfamily has focused on plant MULEs where they were discovered and where some are extremely active and have significant impact on genome structure. The maize MuDR element has been widely used as a tool for both forward and reverse genetic studies because of its high transposition rate and preference for targeting genic regions. However, despite being widespread, only a few active MULEs have been identified, and only one, the rice Os3378, has demonstrated activity in a non-host organism...
2017: Mobile DNA
https://www.readbyqxmd.com/read/28096461/differential-contribution-of-transmembrane-domains-iv-v-vi-and-vii-to-human-angiotensin-ii-type-1-receptor-homomer-formation
#11
Brent M Young, Elaine Nguyen, Matthew A J Chedrawe, Jan K Rainey, Denis J Dupré
G protein-coupled receptors (GPCRs) play an important role in drug therapy, and represent one of the largest families of drug targets. The angiotensin II type 1 receptor (AT1R) is notable as it has a central role in the treatment of cardiovascular disease. Blockade of AT1R signaling has been shown to alleviate hypertension and improve outcomes in patients with heart failure. Despite this, it has become apparent that our initial understanding of AT1R signaling is over-simplified. There is considerable evidence to suggest that AT1R signaling is highly modified in the presence of receptor-receptor interactions, but there is very little structural data available to explain this phenomenon even with the recent elucidation of the AT1R crystal structure...
January 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28095902/identification-of-positive-selection-in-genes-is-greatly-improved-by-using-experimentally-informed-site-specific-models
#12
Jesse D Bloom
BACKGROUND: Sites of positive selection are identified by comparing observed evolutionary patterns to those expected under a null model for evolution in the absence of such selection. For protein-coding genes, the most common null model is that nonsynonymous and synonymous mutations fix at equal rates; this unrealistic model has limited power to detect many interesting forms of selection. RESULTS: I describe a new approach that uses a null model based on experimental measurements of a gene's site-specific amino-acid preferences generated by deep mutational scanning in the lab...
January 17, 2017: Biology Direct
https://www.readbyqxmd.com/read/28095454/non-homologous-end-joining-and-homology-directed-dna-repair-frequency-of-double-stranded-breaks-introduced-by-genome-editing-reagents
#13
Michail Zaboikin, Tatiana Zaboikina, Carl Freter, Narasimhachar Srinivasakumar
Genome editing using transcription-activator like effector nucleases or RNA guided nucleases allows one to precisely engineer desired changes within a given target sequence. The genome editing reagents introduce double stranded breaks (DSBs) at the target site which can then undergo DNA repair by non-homologous end joining (NHEJ) or homology directed recombination (HDR) when a template DNA molecule is available. NHEJ repair results in indel mutations at the target site. As PCR amplified products from mutant target regions are likely to exhibit different melting profiles than PCR products amplified from wild type target region, we designed a high resolution melting analysis (HRMA) for rapid identification of efficient genome editing reagents...
2017: PloS One
https://www.readbyqxmd.com/read/28094803/mir-124-inhibits-the-migration-and-invasion-of-human-hepatocellular-carcinoma-cells-by-suppressing-integrin-%C3%AE-v-expression
#14
Qian Qian Cai, Yi Wei Dong, Rong Wang, Bing Qi, Jun Xia Guo, Jing Pan, Yuan Yuan Liu, Chun Yi Zhang, Xing Zhong Wu
Tumor metastasis is the major cause of cancer-related death especially in human hepatocellular carcinoma (HCC). Although microRNAs have been implicated in tumor development, the roles of miR-124 in HCC metastasis are still not well understood. We conducted functional analysis in this study to investigate miR-124. We observed that miR-124 significantly retarded the wound healing and migration of HCC SMMC-7721 and BEL-7404 cells. Further analysis indicated miR-124 directly targeting the transcriptional factor Sp1 which is an important transcription factor for the integrin αV subunit gene transcription...
January 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28087830/recognition-of-the-magnaporthe-oryzae-effector-avr-pia-by-the-decoy-domain-of-the-rice-nlr-immune-receptor-rga5
#15
Diana Ortiz, Karine De Guillen, Stella Cesari, Véronique Chalvon, Jérome Gracy, André Padilla, Thomas Kroj
Nucleotide-binding domain and leucine-rich repeat proteins (NLRs) are important receptors in plant immunity that allow recognition of pathogen effectors. The rice NLR RGA5 recognizes the Magnaporthe oryzae effector AVR-Pia through direct interaction. Here, we gained detailed insights into the molecular and structural bases of AVR-Pia-RGA5 interaction and the role of the RATX1 decoy domain of RGA5. NMR titration combined with in vitro and in vivo protein-protein interaction analyses identified the AVR-Pia interaction surface that binds to the RATX1 domain...
January 13, 2017: Plant Cell
https://www.readbyqxmd.com/read/28087715/sf3b1-hsh155-heat-motif-mutations-affect-interaction-with-the-spliceosomal-atpase-prp5-resulting-in-altered-branch-site-selectivity-in-pre-mrna-splicing
#16
Qing Tang, Susana Rodriguez-Santiago, Jing Wang, Jia Pu, Andrea Yuste, Varun Gupta, Alberto Moldón, Yong-Zhen Xu, Charles C Query
Mutations in the U2 snRNP component SF3B1 are prominent in myelodysplastic syndromes (MDSs) and other cancers and have been shown recently to alter branch site (BS) or 3' splice site selection in splicing. However, the molecular mechanism of altered splicing is not known. We show here that hsh155 mutant alleles in Saccharomyces cerevisiae, counterparts of SF3B1 mutations frequently found in cancers, specifically change splicing of suboptimal BS pre-mRNA substrates. We found that Hsh155p interacts directly with Prp5p, the first ATPase that acts during spliceosome assembly, and localized the interacting regions to HEAT (Huntingtin, EF3, PP2A, and TOR1) motifs in SF3B1 associated with disease mutations...
December 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/28087622/calmodulin-limits-pathogenic-na-channel-persistent-current
#17
Haidun Yan, Chaojian Wang, Steven O Marx, Geoffrey S Pitt
Increased "persistent" current, caused by delayed inactivation, through voltage-gated Na(+) (NaV) channels leads to cardiac arrhythmias or epilepsy. The underlying molecular contributors to these inactivation defects are poorly understood. Here, we show that calmodulin (CaM) binding to multiple sites within NaV channel intracellular C-terminal domains (CTDs) limits persistent Na(+) current and accelerates inactivation across the NaV family. Arrhythmia or epilepsy mutations located in NaV1.5 or NaV1.2 channel CTDs, respectively, reduce CaM binding either directly or by interfering with CTD-CTD interchannel interactions...
January 13, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28087460/identification-of-the-doublesex-protein-binding-sites-that-activate-expression-of-lozenge-in-the-female-genital-disc-in-drosophila-melanogaster
#18
Shunsuke Wagamitsu, Dan Takase, Fugaku Aoki, Masataka G Suzuki
Normal sexual differentiation in the genital organs is essential for the animal species that use sexual reproduction. Although it is known that doublesex (dsx) is required for the sexual development of the genitalia in various insect species, the direct target genes responsible for the sexual differentiation of the genitalia have not been identified. The lozenge (lz) gene is expressed in the female genital disc and is essential for developments of spermathecae and accessory glands in Drosophila melanogaster...
January 10, 2017: Mechanisms of Development
https://www.readbyqxmd.com/read/28080208/a-research-program-for-the-socioeconomic-impacts-of-gene-editing-regulation
#19
Agustina I Whelan, Martin A Lema
Gene editing technologies are a group of recent innovations in plant breeding using molecular biology, which have in common the capability of introducing a site-directed mutation or deletion in the genome. The first cases of crops improved with these technologies are approaching the market; this has raised an international debate regarding if they should be regulated as genetically modified crops or just as another form of mutagenesis under conventional breeding. This dilemma for policymakers not only entails issues pertaining safety information and legal/regulatory definitions...
January 12, 2017: GM Crops & Food
https://www.readbyqxmd.com/read/28078782/pacmans-a-bioinformatically-informed-algorithm-to-predict-design-and-disrupt-protease-on-protease-hydrolysis
#20
Meghan C Ferrall-Fairbanks, Zachary T Barry, Maurizio Affer, Marc A Shuler, Ellen W Moomaw, Manu O Platt
Multiple proteases in a system hydrolyze target substrates, but recent evidence indicates that some proteases will degrade other proteases as well. Cathepsin S hydrolysis of cathepsin K is one such example. These interactions may be uni- or bi-directional and change the expected kinetics. To explore potential protease-on-protease interactions in silico, a program was developed for users to input two proteases: 1) the protease-ase that hydrolyzes 2) the substrate, protease. This program identifies putative sites on the substrate protease highly susceptible to cleavage by the protease-ase, using a sliding window approach that scores amino acid sequences by their preference in the protease-ase active site, culled from MEROPS database...
January 12, 2017: Protein Science: a Publication of the Protein Society
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