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tRNA Synthetase

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https://www.readbyqxmd.com/read/29784813/coordination-of-the-leucine-sensing-rag-gtpase-cycle-by-leucyl-trna-synthetase-in-the-mtorc1-signaling-pathway
#1
Minji Lee, Jong Hyun Kim, Ina Yoon, Chulho Lee, Mohammad Fallahi Sichani, Jong Soon Kang, Jeonghyun Kang, Min Guo, Kang Young Lee, Gyoonhee Han, Sunghoon Kim, Jung Min Han
A protein synthesis enzyme, leucyl-tRNA synthetase (LRS), serves as a leucine sensor for the mechanistic target of rapamycin complex 1 (mTORC1), which is a central effector for protein synthesis, metabolism, autophagy, and cell growth. However, its significance in mTORC1 signaling and cancer growth and its functional relationship with other suggested leucine signal mediators are not well-understood. Here we show the kinetics of the Rag GTPase cycle during leucine signaling and that LRS serves as an initiating "ON" switch via GTP hydrolysis of RagD that drives the entire Rag GTPase cycle, whereas Sestrin2 functions as an "OFF" switch by controlling GTP hydrolysis of RagB in the Rag GTPase-mTORC1 axis...
May 21, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29783990/severe-hepatopathy-and-neurological-deterioration-after-start-of-valproate-treatment-in-a-6-year-old-child-with-mitochondrial-tryptophanyl-trna-synthetase-deficiency
#2
Elise Vantroys, Joél Smet, Arnaud V Vanlander, Sarah Vergult, Ruth De Bruyne, Frank Roels, Hedwig Stepman, Herbert Roeyers, Björn Menten, Rudy Van Coster
BACKGROUND: The first subjects with deficiency of mitochondrial tryptophanyl-tRNA synthetase (WARS2) were reported in 2017. Their clinical characteristics can be subdivided into three phenotypes (neonatal phenotype, severe infantile onset phenotype, Parkinson-like phenotype). RESULTS: Here, we report on a subject who presented with early developmental delay, motor weakness and intellectual disability and who was considered during several years as having a non-progressive encephalopathy...
May 21, 2018: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/29781997/antimicrobial-peptides-produced-by-selective-pressure-incorporation-of-non-canonical-amino-acids
#3
Jessica H Nickling, Tobias Baumann, Franz-Josef Schmitt, Maike Bartholomae, Oscar P Kuipers, Thomas Friedrich, Nediljko Budisa
Nature has a variety of possibilities to create new protein functions by modifying the sequence of the individual amino acid building blocks. However, all variations are based on the 20 canonical amino acids (cAAs). As a way to introduce additional physicochemical properties into polypeptides, the incorporation of non-canonical amino acids (ncAAs) is increasingly used in protein engineering. Due to their relatively short length, the modification of ribosomally synthesized and post-translationally modified peptides by ncAAs is particularly attractive...
May 4, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29780583/exploring-local-solvation-environments-of-a-heme-protein-using-the-spectroscopic-reporter-4-cyano-l-phenylalanine
#4
Caroline Kearney, Lukasz T Olenginski, Trexler D Hirn, Gwendolyn D Fowler, Daniyal Tariq, Scott H Brewer, Christine M Phillips-Piro
The vibrational reporter unnatural amino acid (UAA) 4-cyano-l-phenylalanine (pCNF) was genetically incorporated individually at three sites (5, 36, and 78) in the heme protein Caldanaerobacter subterraneus H-NOX to probe local hydration environments. The UAA pCNF was incorporated site-specifically using an engineered, orthogonal tRNA synthetase in E. coli . The ability of all of the pCNF-containing H-NOX proteins to form the ferrous CO, NO, or O2 ligated and unligated states was confirmed with UV-Vis spectroscopy...
April 9, 2018: RSC Advances
https://www.readbyqxmd.com/read/29779382/specific-stereoisomeric-conformations-determine-the-drug-potency-of-cladosporin-scaffold-against-malarial-parasite
#5
Pronay Das, Palak Babbar, Nipun Malhotra, Manmohan Sharma, Gorakhnath R Jachak, Rajesh G Gonnade, Dhanasekaran Shanmugam, Karl Harlos, Manickam Yogavel, Amit Sharma, D Srinivasa Reddy
The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral centre anti-malarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme- and structure-based assays. We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency where changes at C3 are sensed by rotameric flipping of Glutamate332...
May 21, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29775242/mutations-in-mars-identified-in-a-specific-type-of-pulmonary-alveolar-proteinosis-alter-methionyl-trna-synthetase-activity
#6
Martine Comisso, Alice Hadchouel, Jacques de Blic, Marc Mirande
Biallelic missense mutations in MARS are responsible for rare but severe cases of pulmonary alveolar proteinosis (PAP) prevalent on the island of La Réunion. MARS encodes cytosolic methionyl-tRNA synthetase (MetRS), an essential translation factor. The multisystemic effects observed in patients with this form of PAP is consistent with a loss-of-function defect in an ubiquitously expressed enzyme. The pathophysiological mechanisms involved in MARS related PAP are currently unknown. In this work, we analyzed the effect of the PAP related mutations in MARS on the thermal stability and on the catalytic parameters of the MetRS mutants, relative to wild-type...
May 18, 2018: FEBS Journal
https://www.readbyqxmd.com/read/29775058/multiple-click-selective-trna-synthetases-expand-mammalian-cell-specific-proteomics
#7
Andrew C Yang, Haley du Bois, Niclas Olsson, David Gate, Benoit Lehallier, Daniela Berdnik, Kyle D Brewer, Carolyn R Bertozzi, Joshua E Elias, Tony Wyss-Coray
Bio-orthogonal tools enable cell-type-specific proteomics, a prerequisite to understanding biological processes in multicellular organisms. Here we report two engineered aminoacyl-tRNA synthetases for mammalian bio-orthogonal labeling: a tyrosyl ( ScTyrY34G ) and a phenylalanyl ( MmPheT412G ) tRNA synthetase that incorporate azide-bearing noncanonical amino acids specifically into the nascent proteomes of host cells. Azide-labeled proteins are chemoselectively tagged via azide-alkyne cycloadditions with fluorophores for imaging or affinity resins for mass spectrometric characterization...
May 18, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29769718/ankrd16-prevents-neuron-loss-caused-by-an-editing-defective-trna-synthetase
#8
My-Nuong Vo, Markus Terrey, Jeong Woong Lee, Bappaditya Roy, James J Moresco, Litao Sun, Hongjun Fu, Qi Liu, Thomas G Weber, John R Yates, Kurt Fredrick, Paul Schimmel, Susan L Ackerman
Editing domains of aminoacyl tRNA synthetases correct tRNA charging errors to maintain translational fidelity. A mutation in the editing domain of alanyl tRNA synthetase (AlaRS) in Aars sti mutant mice results in an increase in the production of serine-mischarged tRNAAla and the degeneration of cerebellar Purkinje cells. Here, using positional cloning, we identified Ankrd16, a gene that acts epistatically with the Aars sti mutation to attenuate neurodegeneration. ANKRD16, a vertebrate-specific protein that contains ankyrin repeats, binds directly to the catalytic domain of AlaRS...
May 16, 2018: Nature
https://www.readbyqxmd.com/read/29768275/predictive-factors-for-the-long-term-deterioration-of-pulmonary-function-in-interstitial-lung-disease-associated-with-anti-aminoacyl-trna-synthetase-antibodies
#9
Hideaki Yamakawa, Eri Hagiwara, Hideya Kitamura, Tae Iwasawa, Ryota Otoshi, Naoto Aiko, Takuma Katano, Ryota Shintani, Satoshi Ikeda, Ryo Okuda, Akimasa Sekine, Tomohisa Baba, Shinichiro Iso, Kazuyoshi Kuwano, Shinji Sato, Takashi Ogura
BACKGROUND: Little has been reported on long-term pulmonary function trends among patients with interstitial lung disease associated with anti-aminoacyl-tRNA synthetase antibodies (ARS-ILD). OBJECTIVES: To clarify the factors predictive of progression in ARS-ILD based on patients' initial clinical and radiological features. METHODS: The clinical courses of 88 patients with > 1 year of follow-up data on pulmonary function tests (PFTs) were retrospectively analyzed...
May 16, 2018: Respiration; International Review of Thoracic Diseases
https://www.readbyqxmd.com/read/29748969/persulfide-synthases-function-coupled-with-translation-and-mediate-sulfur-respiration
#10
REVIEW
Shigemoto Fuji, Tomohiro Sawa, Hozumi Motohashi, Takaaki Akaike
Cysteine persulfide and polysulfide are produced in cells and exist in abundance in both low-molecular-weight and protein fractions. However, the mechanism of regulation of the formation of cellular cysteine polysulfides and the physiological functions of cysteine persulfides/polysulfides produced in cells are not fully understood. We recently demonstrated that cysteinyl-tRNA synthetase (CARS) is novel cysteine persulfide synthase. CARS is involved in protein polysulfidation that is coupled with translation...
May 10, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29744287/a-noncanonical-function-of-histidyl-trna-synthetase-inhibition-of-vascular-hyperbranching-during-zebrafish-development
#11
Rui Ni, Lingfei Luo
Histidyl-tRNA synthetase (Hars) catalyzes the ligation of histidine residues to cognate tRNA. Here, we demonstrate a noncanonical function of Hars in vascular development in zebrafish. We obtained a novel zebrafish cq34 mutant which exhibited hyperbranching of cranial and intersegmental blood vessels 48 h after fertilization. The gene responsible for this phenotype was identified as hars . We found the increased expression of cdh5 and vegfa in the hars cq34 mutant. Knockdown of cdh5 in the mutant reduced disordered connections of the hindbrain capillaries...
May 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29727262/aminoacyl-trna-synthetase-evolution-and-sectoring-of-the-genetic-code
#12
Daewoo Pak, Yunsoo Kim, Zachary F Burton
The genetic code sectored via tRNA charging errors, and the code progressed toward closure and universality because of evolution of aminoacyl-tRNA synthetase (aaRS) and ribosome fidelity mechanisms. Class I and class II aaRS folds are identified as homologs. Five mechanisms toward code closure are highlighted: 1) aaRS proofreading to remove mischarged amino acids from tRNA; 2) accurate aaRS active site specification of amino acid substrates; 3) aaRS-tRNA anticodon recognition; 4) EF-TU and GTP hydrolysis proofreading of the tRNA-mRNA interaction; and 5) modification of tRNA wobble adenine to inosine...
May 4, 2018: Transcription
https://www.readbyqxmd.com/read/29723968/11th-iubmb-focused-meeting-on-the-aminoacyl-trna-synthetases-sailing-a-new-sea-of-complex-functions-in-human-biology-and-disease
#13
Christopher Francklyn, Herve Roy, Rebecca Alexander
The 11th IUBMB Focused Meeting on Aminoacyl-tRNA Synthetases was held in Clearwater Beach, Florida from 29 October⁻2 November 2017, with the aim of presenting the latest research on these enzymes and promoting interchange among aminoacyl-tRNA synthetase (ARS) researchers. Topics covered in the meeting included many areas of investigation, including ARS evolution, mechanism, editing functions, biology in prokaryotic and eukaryotic cells and their organelles, their roles in human diseases, and their application to problems in emerging areas of synthetic biology...
May 1, 2018: Biomolecules
https://www.readbyqxmd.com/read/29723545/reversible-inactivation-of-yeast-mitochondrial-phenylalanyl-trna-synthetase-under-oxidative-stress
#14
Shruti Chakraborty, Sayak Ganguli, Aritra Chowdhury, Michael Ibba, Rajat Banerjee
BACKGROUND: Under oxidative stress cytoplasmic aminoacyl-tRNA synthetase (aaRSs) substrate specificity can be compromised, leading to tRNA mischarging and mistranslation of the proteome. Whether similar processes occur in mitochondria, which are major cellular sources of reactive oxygen species (ROS), is unknown. However, relaxed substrate specificity in yeast mitochondrial phenylalanyl-tRNA synthetase (ScmitPheRS) has been reported to increase tRNA mischarging and blocks mitochondrial biogenesis...
April 30, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29720556/a-rice-glutamyl-trna-synthetase-modulates-early-anther-cell-division-and-patterning
#15
Xiujuan Yang, Gang Li, Yuesheng Tian, Yu Song, Wanqi Liang, Dabing Zhang
In organisms, aminoacyl-tRNA synthetases (aaRSs) play a housekeeping role in cellular protein synthesis, but little is understood about how these aaRSs are involved in organ development. Here we report that, in the model crop rice (Oryza sativa), a glutamyl-tRNA synthetase (OsERS1) maintains proper somatic cell organization and limits the over-proliferation of male germinal cells during early anther development. The expression of OsERS1 is specifically detectable in meristematic layer 2-derived (L2-d) cells of the early anther, and osers1 exhibits over-proliferation and disorganization of L2-d cells, producing fused lobes and extra germinal cells in early anthers...
May 2, 2018: Plant Physiology
https://www.readbyqxmd.com/read/29694026/directed-evolution-of-heterologous-trnas-leads-to-reduced-dependence-on-post-transcriptional-modifications
#16
Kevin C Baldridge, Manasses Jora, Andre C Maranhao, Matthew M Quick, Balasubrahmanyam Addepalli, Jennifer S Brodbelt, Andrew D Ellington, Patrick A Limbach, Lydia M Contreras
Heterologous tRNA:aminoacyl tRNA synthetase pairs are often employed for noncanonical amino acid incorporation in the quest for an expanded genetic code. In this work, we investigated one possible mechanism by which directed evolution can improve orthogonal behavior for a suite of Methanocaldococcus jannaschii ( Mj) tRNATyr -derived amber suppressor tRNAs. Northern blotting demonstrated that reduced expression of heterologous tRNA variants correlated with improved orthogonality. We suspected that reduced expression likely minimized nonorthogonal interactions with host cell machinery...
April 25, 2018: ACS Synthetic Biology
https://www.readbyqxmd.com/read/29691655/loss-of-function-mutations-in-vars-encoding-cytoplasmic-valyl-trna-synthetase-cause-microcephaly-seizures-and-progressive-cerebral-atrophy
#17
Joshi Stephen, Sheela Nampoothiri, Aditi Banerjee, Nathanial J Tolman, Josef Martin Penninger, Ullrich Elling, Chukwuma A Agu, John D Burke, Kalpana Devadathan, Rajesh Kannan, Yan Huang, Peter J Steinbach, Susan A Martinis, William A Gahl, May Christine V Malicdan
Progressive microcephaly and neurodegeneration are genetically heterogenous conditions, largely associated with genes that are essential for the survival of neurons. In this study, we interrogate the genetic etiology of two siblings from a non-consanguineous family with severe early onset of neurological manifestations. Whole exome sequencing identified novel compound heterozygous mutations in VARS that segregated with the proband: a missense (c.3192G>A; p.Met1064Ile) and a splice site mutation (c.1577-2A>G)...
April 24, 2018: Human Genetics
https://www.readbyqxmd.com/read/29683449/optimizing-the-genetic-incorporation-of-chemical-probes-into-gpcrs-for-photo-crosslinking-mapping-and-bioorthogonal-chemistry-in-live-mammalian-cells
#18
Robert Serfling, Lisa Seidel, Thore Böttke, Irene Coin
The genetic incorporation of non-canonical amino acids (ncAAs) via amber stop codon suppression is a powerful technique to install artificial probes and reactive moieties onto proteins directly in the live cell. Each ncAA is incorporated by a dedicated orthogonal suppressor-tRNA/amino-acyl-tRNA-synthetase (AARS) pair that is imported into the host organism. The incorporation efficiency of different ncAAs can greatly differ, and be unsatisfactory in some cases. Orthogonal pairs can be improved by manipulating either the AARS or the tRNA...
April 9, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29681891/expanding-the-genetic-code-of-lactococcus-lactis-and-escherichia-coli-to-incorporate-non-canonical-amino-acids-for-production-of-modified-lantibiotics
#19
Maike Bartholomae, Tobias Baumann, Jessica H Nickling, David Peterhoff, Ralf Wagner, Nediljko Budisa, Oscar P Kuipers
The incorporation of non-canonical amino acids (ncAAs) into ribosomally synthesized and post-translationally modified peptides, e.g., nisin from the Gram-positive bacterium Lactococcus lactis , bears great potential to expand the chemical space of various antimicrobials. The ncAA N ε -Boc-L-lysine (BocK) was chosen for incorporation into nisin using the archaeal pyrrolysyl-tRNA synthetase-tRNAPyl pair to establish orthogonal translation in L. lactis for read-through of in-frame amber stop codons. In parallel, recombinant nisin production and orthogonal translation were combined in Escherichia coli cells...
2018: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29679766/aminoacyl-trna-synthetase-complex-interacting-multifunctional-protein-1-simultaneously-binds-glutamyl-prolyl-trna-synthetase-and-scaffold-protein-aminoacyl-trna-synthetase-complex-interacting-multifunctional-protein-3-of-the-multi-trna-synthetase-complex
#20
Margaret A Schwarz, Daniel D Lee, Seamus Bartlett
Higher eukaryotes have developed extensive compartmentalization of amino acid (aa) - tRNA coupling through the formation of a multi-synthetase complex (MSC) that is composed of eight aa-tRNA synthetases (ARS) and three scaffold proteins: aminoacyl tRNA synthetase complex interacting multifunctional proteins (AIMP1, 2 and 3). Lower eukaryotes have a much smaller complex while yeast MSC consists of only two ARS (MetRS and GluRS) and one ARS cofactor 1 protein, Arc1p (Simos et al., 1996), the homolog of the mammalian AIMP1...
April 18, 2018: International Journal of Biochemistry & Cell Biology
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