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tRNA Synthetase

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https://www.readbyqxmd.com/read/28641210/comparative-analysis-of-polyspecificity-of-the-endogenous-trna-synthetase-of-different-expression-host-towards-photocrosslinking-amino-acids-using-an-in-silico-approach
#1
Nadarajan Saravanan Prabhu, Hyungdon Yun
Photo-induced covalent crosslinking has emerged as the powerful strategy for analyzing and characterizing the protein-protein interaction and mapping protein 3D conformations. In the last decades, a number of photocrosslinking amino acids have been reported but only a few have been efficiently utilized for photocrosslinking purposes. Recently, incorporation of diazirine containing photoactivatable analogs such as photo-methionine, photo-leucine, photo-isoleucine and photo-lysine into target proteins were accomplished in live cells (Human A549cells, HEK 293) by depleting corresponding natural amino acid and supplementing these analogs in the medium...
June 8, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28633377/emerging-mechanisms-of-aminoacyl-trna-synthetase-mutations-in-recessive-and-dominant-human-disease
#2
Rebecca Meyer-Schuman, Anthony Antonellis
Aminoacyl-tRNA synthetases (ARSs) are responsible for charging amino acids to cognate tRNA molecules, which is the essential first step of protein translation. Interestingly, mutations in genes encoding ARS enzymes have been implicated in a broad spectrum of human inherited diseases. Bi-allelic mutations in ARSs typically cause severe, early-onset, recessive diseases that affect a wide range of tissues. The vast majority of these mutations show loss-of-function effects and impair protein translation. However, it is not clear how a subset cause tissue-specific phenotypes...
June 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28632987/the-usher-syndrome-type-iiib-histidyl-trna-synthetase-mutation-confers-temperature-sensitivity
#3
Jamie A Abbott, Ethan Guth, Cindy Kim, Cathy Regan, Victoria M Siu, Charles Anthony Rupar, Borries Demeler, Christopher S Francklyn, Susan M Robey-Bond
Histidyl-tRNA synthetase (HARS) is a highly conserved translation factor that plays an essential role in protein synthesis. HARS has been implicated in the human syndromes Charcot-Marie-Tooth (CMT) Type 2W and Type IIIB Usher (USH3B). The USH3B mutation, which encodes an Y454S substitution in HARS, is inherited in an autosomal recessive fashion and associated with childhood deafness, blindness and episodic hallucinations during acute illness. The biochemical basis of the pathophysiologies linked to USH3B is currently unknown...
June 20, 2017: Biochemistry
https://www.readbyqxmd.com/read/28626001/krs-a-cut-away-from-release-in-exosomes
#4
Catherine Rabouille
Cancer cells often trigger an inflammatory process, which in some cases may be driven by the presence of lysyl-tRNA synthetase (KRS) in the medium. Kim et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201605118) now demonstrate that cleavage of the KRS by caspase-8 inside cells triggers its interaction with syntenin and its release in inflammatory exosomes.
June 16, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28625715/discovery-of-simplified-leucyladenylate-sulfamates-as-novel-leucyl-trna-synthetase-lrs-targeted-mammalian-target-of-rapamycin-complex-1-mtorc1-inhibitors
#5
Suyoung Yoon, Jong Hyun Kim, Yura Koh, Phuong-Thao Tran, Jihyae Ann, Ina Yoon, Jayun Jang, Won Kyung Kim, Sangkook Lee, Jiyoun Lee, Sunghoon Kim, Jeewoo Lee
Leucyl-tRNA synthetase (LRS) has been reported to be a possible mediator of intracellular amino acids signaling to mTORC1. Given that mTORC1 is associated with cell proliferation and tumorigenesis, the LRS-mediated mTORC1 pathway may offer an alternative strategy in anticancer therapy. In this study, we developed a series of simplified analogues of leucyladenylate sulfamate (1) as LRS-targeted mTORC1 inhibitors. We replaced the adenylate group with a N-(3,4-dimethoxybenzyl)benzenesulfonamide (2a) or a N-(2-phenoxyethyl)benzenesulfonamide groups (2b) that can maintain specific binding, but has more favorable physicochemical properties such as reduced polarity and asymmetric centers...
June 2, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28621923/capture-and-release-of-trna-by-the-t-loop-receptor-in-the-function-of-the-t-box-riboswitch
#6
Xianyang Fang, Malgorzata Michnicka, Yikan Zhang, Yun Xing Wang, Edward P Nikonowicz
In Gram-positive bacteria, the tRNA-dependent T-box riboswitch system regulates expression of amino acid biosynthetic and aminoacyl-tRNA synthetase genes through a transcription attenuation mechanism. Binding of uncharged tRNA "closes" the switch, allowing transcription read-through. Structure studies of the 100 nt stem I domain reveal tRNA utilizes base pairing and stacking interactions to bind the stem, but little is known structurally about the 180 nt riboswitch core (stem I, stem III, and antiterminator stem) in complex with tRNA and the mechanism of coupling of the intermolecular binding domains crucial to T-box function...
June 16, 2017: Biochemistry
https://www.readbyqxmd.com/read/28620870/severe-growth-deficiency-microcephaly-intellectual-disability-and-characteristic-facial-features-are-due-to-a-homozygous-qars-mutation
#7
Esther Leshinsky-Silver, Jiqiang Ling, Jiang Wu, Chana Vinkler, Keren Yosovich, Sarit Bahar, Miri Yanoov-Sharav, Tally Lerman-Sagie, Dorit Lev
Glutaminyl tRNA synthase is highly expressed in the developing fetal human brain. Mutations in the glutaminyl-tRNA synthetase (QARS) gene have been reported in patients with progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. We have previously reported a new recessive syndrome of severe linear growth retardation, poor weight gain, microcephaly, characteristic facial features, cutaneous syndactyly of the toes, high myopia, and intellectual disability in two sisters of Ashkenazi-Jewish origin (Eur J Med Genet 2014;57(6):288-92)...
June 15, 2017: Neurogenetics
https://www.readbyqxmd.com/read/28616572/reversible-lysine-acetylation-regulates-nuclear-translocation-of-tyrrs-to-counteract-genotoxic-oxidative-stress
#8
Chaoqun Li, Wei Yu
Aminoacyl-tRNA synthetases, catalyzing the first step of protein synthesis, have been shown to involve with multiple additional physiologic responses. Here, we summarize our findings that p300/CBP-Associated Factor and Sirtuin 1 play the reversible acetylation role in regulating the nuclear translocation of Tyrosyl-tRNA synthetase and activating transcription factor E2F1, thus facilitating the repair of damaged DNA.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/28611052/caspase-8-controls-the-secretion-of-inflammatory-lysyl-trna-synthetase-in-exosomes-from-cancer-cells
#9
Sang Bum Kim, Hye Rim Kim, Min Chul Park, Seongmin Cho, Peter C Goughnour, Daeyoung Han, Ina Yoon, YounHa Kim, Taehee Kang, Eunjoo Song, Pilhan Kim, Hyosun Choi, Ji Young Mun, Chihong Song, Sangmin Lee, Hyun Suk Jung, Sunghoon Kim
Aminoacyl-tRNA synthetases (ARSs), enzymes that normally control protein synthesis, can be secreted and have different activities in the extracellular space, but the mechanism of their secretion is not understood. This study describes the secretion route of the ARS lysyl-tRNA synthetase (KRS) and how this process is regulated by caspase activity, which has been implicated in the unconventional secretion of other proteins. We show that KRS is secreted from colorectal carcinoma cells within the lumen of exosomes that can trigger an inflammatory response...
June 13, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28608946/genetic-encoding-of-photocaged-tyrosines-with-improved-light-activation-properties-for-the-optical-control-of-protease-function
#10
Ji Luo, Jessica Torres-Kolbus, Jihe Liu, Alexander Deiters
We genetically encoded three new caged tyrosine analogues with improved photochemical properties by using an engineered pyrrolysyl-tRNA synthetase/tRNACUA pair in bacterial and mammalian cells. We applied the new tyrosine analogues to the photoregulation of firefly luciferase by caging its key tyrosine residue, Tyr340, and observed excellent off-to-on light switching. This reporter was then used to evaluate the activation rates of the different light-removable protecting groups in live cells. We identified the nitropiperonyl caging group as an excellent compromise between incorporation efficiency and photoactivation properties...
June 13, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28608363/misynpat-an-integrated-knowledge-base-linking-clinical-genetic-and-structural-data-for-disease-causing-mutations-in-human-mitochondrial-aminoacyl-trna-synthetases
#11
Luc Moulinier, Raymond Ripp, Gaston Castillo, Olivier Poch, Marie Sissler
Numerous mutations in each of the mitochondrial aminoacyl-tRNA synthetases have been implicated in human diseases. The mutations are autosomal and recessive and lead mainly to neurological disorders, although with pleiotropic effects. The processes and interactions that drive the etiology of the disorders associated with mitochondrial aminoacyl-tRNA synthetases are far from understood. The complexity of the clinical, genetic and structural data requires concerted, interdisciplinary efforts to understand the molecular biology of these disorders...
June 12, 2017: Human Mutation
https://www.readbyqxmd.com/read/28605379/voltage-clamp-fluorometry-in-xenopus-oocytes-using-fluorescent-unnatural-amino-acids
#12
Tanja Kalstrup, Rikard Blunck
Voltage-Clamp Fluorometry (VCF) has been the technique of choice to investigate the structure and function of electrogenic membrane proteins where real-time measurements of fluorescence and currents simultaneously report on local rearrangements and global function, respectively(1). While high-resolution structural techniques such as cryo-electron microscopy or X-ray crystallography provide static images of the proteins of interest, VCF provides dynamic structural data that allows us to link the structural rearrangements (fluorescence) to dynamic functional data (electrophysiology)...
May 27, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28604693/genetically-encoding-phosphotyrosine-and-its-nonhydrolyzable-analog-in-bacteria
#13
Xiaozhou Luo, Guangsen Fu, Rongsheng E Wang, Xueyong Zhu, Claudio Zambaldo, Renhe Liu, Tao Liu, Xiaoxuan Lyu, Jintang Du, Weimin Xuan, Anzhi Yao, Sean A Reed, Mingchao Kang, Yuhan Zhang, Hui Guo, Chunhui Huang, Peng-Yu Yang, Ian A Wilson, Peter G Schultz, Feng Wang
Tyrosine phosphorylation is a common protein post-translational modification that plays a critical role in signal transduction and the regulation of many cellular processes. Using a propeptide strategy to increase cellular uptake of O-phosphotyrosine (pTyr) and its nonhydrolyzable analog 4-phosphomethyl-L-phenylalanine (Pmp), we identified an orthogonal aminoacyl-tRNA synthetase-tRNA pair that allows site-specific incorporation of both pTyr and Pmp into recombinant proteins in response to the amber stop codon in Escherichia coli in good yields...
June 12, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28594869/compound-heterozygous-mutations-in-glycyl-trna-synthetase-gars-cause-mitochondrial-respiratory-chain-dysfunction
#14
Michael Nafisinia, Lisa G Riley, Wendy A Gold, Kaustuv Bhattacharya, Carolyn R Broderick, David R Thorburn, Cas Simons, John Christodoulou
Glycyl-tRNA synthetase (GARS; OMIM 600287) is one of thirty-seven tRNA-synthetase genes that catalyses the synthesis of glycyl-tRNA, which is required to insert glycine into proteins within the cytosol and mitochondria. To date, eighteen mutations in GARS have been reported in patients with autosomal-dominant Charcot-Marie-Tooth disease type 2D (CMT2D; OMIM 601472), and/or distal spinal muscular atrophy type V (dSMA-V; OMIM 600794). In this study, we report a patient with clinical and biochemical features suggestive of a mitochondrial respiratory chain (MRC) disorder including mild left ventricular posterior wall hypertrophy, exercise intolerance, and lactic acidosis...
2017: PloS One
https://www.readbyqxmd.com/read/28594177/a-versatile-toolbox-for-the-control-of-protein-levels-using-n-%C3%AE%C2%B5-acetyl-l-lysine-dependent-amber-suppression
#15
Wolfram Volkwein, Christopher Maier, Ralph Krafczyk, Kirsten Jung, Jürgen Lassak
The analysis of the function of essential genes in vivo depends on the ability to experimentally modulate levels of their protein products. Current methods to address this are based on transcriptional or post-transcriptional regulation of mRNAs but approaches based on the exploitation of translational regulation have so far been neglected. Here we describe a toolbox, based on amber suppression in the presence of Nε-acetyl-L-lysine (AcK), for translational tuning of protein output. We chose the highly sensitive luminescence system LuxCDABE as a reporter and incorporated a UAG stop codon into the gene for the reductase subunit LuxC...
June 8, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28592109/the-roles-of-the-active-site-zn-ii-and-residues-in-substrate-discrimination-by-threonyl-trna-synthetase-an-md-and-qm-mm-investigation
#16
Mohamed M Aboelnga, James Wilson Gauld
Threonyl-tRNA synthetase (ThrRS) is a Zn(II) containing enzyme that catalyzes the activation of threonine and its subsequent transfer to the cognate tRNA. This process is accomplished with remarkable fidelity, with ThrRS being able to discriminate its cognate substrate from similar analogs such as serine and valine. Molecular dynamics (MD) simulations and hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) methods have been used to elucidate the role of Zn(II) in the aminoacylation mechanism of ThrRS. More specifically, the role of Zn(II) and active site residues in ThrRS's ability to discriminate between its cognate substrate L-threonine, and the non-cognate L-serine, L-valine and D-threonine has been examined...
June 7, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28591743/serine-207-phosphorylated-lysyl-trna-synthetase-predicts-disease-free-survival-of-non-small-cell-lung-carcinoma
#17
Suliman Boulos, Min Chul Park, Marian Zeibak, Shen Yun Foo, Yoon Kyung Jeon, Young Tae Kim, Alex Motzik, Sagi Tshori, Tamar Hamburger, Sunghoon Kim, Hovav Nechushtan, Ehud Razin
It has been shown that various tRNA synthetases exhibit non-canonical activities unrelated to their original role in translation. We have previously described a signal transduction pathway in which serine 207 phosphorylated lysyl-tRNA synthetase (P-s207 LysRS) is released from the cytoplasmic multi-tRNA synthetase complex (MSC) into the nucleus, where it activates the transcription factor MITF in stimulated cultured mast cells and cardiomyocytes. Here we describe a similar transformation of LysRS due to EGFR signaling activation in human lung cancer...
May 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28589220/binding-properties-of-split-trna-to-the-c-terminal-domain-of-methionyl-trna-synthetase-of-nanoarchaeum-equitans
#18
Hidemichi Suzuki, Akihiro Kaneko, Taro Yamamoto, Mahoko Nambo, Ito Hirasawa, Takuya Umehara, Hisashi Yoshida, Sam-Yong Park, Koji Tamura
The C-terminal domain of methionyl-tRNA synthetase (MetRS-C) from Nanoarchaeum equitans is homologous to a tRNA-binding protein consisting of 111 amino acids (Trbp111) from Aquifex aeolicus. The crystal structure of MetRS-C showed that it existed as a homodimer, and that each monomer possessed an oligonucleotide/oligosaccharide-binding fold (OB-fold). Analysis using a quartz crystal microbalance indicated that MetRS-C freshly isolated from N. equitans was bound to tRNA. However, binding of the split 3'-half tRNA species was stronger than that of the 5'-half species...
June 6, 2017: Journal of Molecular Evolution
https://www.readbyqxmd.com/read/28584140/safety-tolerability-systemic-exposure-and-metabolism-of-crs3123-a-methionyl-trna-synthetase-inhibitor-developed-for-treatment-of-clostridium-difficile-infections-in-a-phase-i-study
#19
Seema U Nayak, J McLeod Griffiss, Jeffrey Blumer, Mary Ann O'Riordan, Wesley Gray, Robin McKenzie, Robert A Jurao, Amanda T An, Melissa Le, Stacie J Bell, Urs A Ochsner, Thale C Jarvis, Nebojsa Janjic, Jonathan M Zenilman
Clostridium difficile causes antibiotic associated diarrhea and is a major public health concern. Current therapies disrupt the protective intestinal flora, do not reliably prevent recurrent infections and will be decreasingly effective should less susceptible strains emerge. CRS3123 is an oral agent that inhibits bacterial methionyl-tRNA synthetase, has potent activity against C. difficile and aerobic Gram positive bacteria, but little activity against Gram negative bacteria, including anaerobes. This first-in-human, double-blind, placebo-controlled, dose-escalation study evaluated the safety and systemic exposure of CRS3123 after a single oral dose in healthy adults...
June 5, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28576772/incompatibility-between-mitochondrial-and-nuclear-genomes-during-oogenesis-results-in-ovarian-failure-and-embryonic-lethality
#20
Chunyang Zhang, Kristi L Montooth, Brian R Calvi
Mitochondrial dysfunction can cause female infertility. An important remaining question is the extent to which incompatibility between mitochondrial and nuclear genomes contributes to female infertility. It was previously shown that a mitochondrial haplotype from D. simulans (simw(501) ) is incompatible with a nuclear genome from the D. melanogaster strain Oregon-R (OreR), resulting in impaired development, which was enhanced at higher temperature. This mito-nuclear incompatibility is between alleles of the nuclear-encoded mitochondrial tyrosyl- tRNA synthetase (Aatm) and the mitochondrial-encoded tyrosyl-tRNA that it aminoacylates...
June 2, 2017: Development
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