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https://www.readbyqxmd.com/read/28436469/a-novel-method-to-evaluate-ribosomal-performance-in-cell-free-protein-synthesis-systems
#1
Noémie Kempf, Cristina Remes, Ralph Ledesch, Tina Züchner, Henning Höfig, Ilona Ritter, Alexandros Katranidis, Jörg Fitter
Cell-free protein synthesis (CFPS) systems were designed to produce proteins with a minimal set of purified components, thus offering the possibility to follow translation as well as protein folding. In order to characterize the performance of the ribosomes in such a system, it is crucial to separately quantify the two main components of productivity, namely the fraction of active ribosomes and the number of synthesizing cycles. Here, we provide a direct and highly reliable measure of ribosomal activity in any given CFPS system, introducing an enhanced-arrest peptide variant...
April 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28419786/toward-the-rational-design-of-macrolide-antibiotics-to-combat-resistance
#2
Anna Pavlova, Jerry M Parks, Adegboyega K Oyelere, James C Gumbart
Macrolides, one of the most prescribed classes of antibiotics, bind in the bacterial ribosome's polypeptide exit tunnel and inhibit translation. However, mutations and other ribosomal modifications, especially to the base A2058 of the 23S rRNA, have led to a growing resistance problem. Here, we have used molecular dynamics simulations to study the macrolides erythromycin and azithromycin in wild-type, A2058G-mutated, and singly or doubly A2058-methylated E. coli ribosomes. We find that the ribosomal modifications result in less favorable interactions between the base 2058 and the desosamine sugar of the macrolides, as well as greater displacement of the macrolides from their crystal structure position, illuminating the causes of resistance...
April 17, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28416671/case-for-the-genetic-code-as-a-triplet-of-triplets
#3
Fabienne F V Chevance, Kelly T Hughes
The efficiency of codon translation in vivo is controlled by many factors, including codon context. At a site early in the Salmonella flgM gene, the effects on translation of replacing codons Thr6 and Pro8 of flgM with synonymous alternates produced a 600-fold range in FlgM activity. Synonymous changes at Thr6 and Leu9 resulted in a twofold range in FlgM activity. The level of FlgM activity produced by any codon arrangement was directly proportional to the degree of in vivo ribosome stalling at synonymous codons...
April 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28400511/shprh-regulates-rrna-transcription-by-recognizing-the-histone-code-in-an-mtor-dependent-manner
#4
Deokjae Lee, Jungeun An, Young-Un Park, Hungjiun Liaw, Roger Woodgate, Jun Hong Park, Kyungjae Myung
Many DNA repair proteins have additional functions other than their roles in DNA repair. In addition to catalyzing PCNA polyubiquitylation in response to the stalling of DNA replication, SHPRH has the additional function of facilitating rRNA transcription by localizing to the ribosomal DNA (rDNA) promoter in the nucleoli. SHPRH was recruited to the rDNA promoter using its plant homeodomain (PHD), which interacts with histone H3 when the fourth lysine of H3 is not trimethylated. SHPRH enrichment at the rDNA promoter was inhibited by cell starvation, by treatment with actinomycin D or rapamycin, or by depletion of CHD4...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28392174/eif5a-functions-globally-in-translation-elongation-and-termination
#5
Anthony P Schuller, Colin Chih-Chien Wu, Thomas E Dever, Allen R Buskirk, Rachel Green
The eukaryotic translation factor eIF5A, originally identified as an initiation factor, was later shown to promote translation elongation of iterated proline sequences. Using a combination of ribosome profiling and in vitro biochemistry, we report a much broader role for eIF5A in elongation and uncover a critical function for eIF5A in termination. Ribosome profiling of an eIF5A-depleted strain reveals a global elongation defect, with abundant ribosomes stalling at many sequences, not limited to proline stretches...
April 20, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28369621/critical-23s-rrna-interactions-for-macrolide-dependent-ribosome-stalling-on-the-ermcl-nascent-peptide-chain
#6
Miriam Koch, Jessica Willi, Ugo Pradère, Jonathan Hall, Norbert Polacek
The nascent peptide exit tunnel has recently been identified as a functional region of ribosomes contributing to translation regulation and co-translational protein folding. Inducible expression of the erm resistance genes depends on ribosome stalling at specific codons of an upstream open reading frame in the presence of an exit tunnel-bound macrolide antibiotic. The molecular basis for this translation arrest is still not fully understood. Here, we used a nucleotide analog interference approach to unravel important functional groups on 23S rRNA residues in the ribosomal exit tunnel for ribosome stalling on the ErmC leader peptide...
March 21, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28363900/computational-analysis-of-nascent-peptides-that-induce-ribosome-stalling-and-their-proteomic-distribution-in-saccharomyces-cerevisiae
#7
Renana Sabi, Tamir Tuller
Interactions between the ribosomal exit tunnel and the nascent peptide can affect translation elongation rates. While previous studies have already demonstrated the feasibility of such interactions, little is known about the nature of the stalling peptide sequences and their distribution in the proteome. Here we ask which peptide sequences tend to occupy the tunnel of stalled ribosomes and how they are distributed in the proteome. Using computational analysis of ribosome profiling data from S. cerevisiae, we identified for the first time dozens of short stalling peptide sequences and studied their statistical properties...
March 31, 2017: RNA
https://www.readbyqxmd.com/read/28348246/mechanism-of-transcription-initiation-and-promoter-escape-by-e-coli-rna-polymerase
#8
Kate L Henderson, Lindsey C Felth, Cristen M Molzahn, Irina Shkel, Si Wang, Munish Chhabra, Emily F Ruff, Lauren Bieter, Joseph E Kraft, M Thomas Record
To investigate roles of the discriminator and open complex (OC) lifetime in transcription initiation by Escherichia coli RNA polymerase (RNAP; α2ββ'ωσ(70)), we compare productive and abortive initiation rates, short RNA distributions, and OC lifetime for the λPR and T7A1 promoters and variants with exchanged discriminators, all with the same transcribed region. The discriminator determines the OC lifetime of these promoters. Permanganate reactivity of thymines reveals that strand backbones in open regions of long-lived λPR-discriminator OCs are much more tightly held than for shorter-lived T7A1-discriminator OCs...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28323820/selective-stalling-of-human-translation-through-small-molecule-engagement-of-the-ribosome-nascent-chain
#9
Nathanael G Lintner, Kim F McClure, Donna Petersen, Allyn T Londregan, David W Piotrowski, Liuqing Wei, Jun Xiao, Michael Bolt, Paula M Loria, Bruce Maguire, Kieran F Geoghegan, Austin Huang, Tim Rolph, Spiros Liras, Jennifer A Doudna, Robert G Dullea, Jamie H D Cate
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in regulating the levels of plasma low-density lipoprotein cholesterol (LDL-C). Here, we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by inducing the ribosome to stall around codon 34, mediated by the sequence of the nascent chain within the exit tunnel. We further show that PF-06446846 reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. Using ribosome profiling, we demonstrate that PF-06446846 is highly selective for the inhibition of PCSK9 translation...
March 2017: PLoS Biology
https://www.readbyqxmd.com/read/28320876/taking-a-step-back-from-back-translocation-an-integrative-view-of-lepa-ef4-s-cellular-function
#10
Jalyce L E Heller, Rajashekhar Kamalampeta, Hans-Joachim Wieden
Protein synthesis, the translation of mRNA into a polypeptide facilitated by the ribosome, is assisted by a variety of protein factors, some of which are GTPases. In addition to four highly conserved and well-understood GTPases with known function, there are also a number of non-canonical GTPases that are implicated in translation but whose functions are not fully understood. LepA/EF4 is one of these non-canonical GTPases. It is highly conserved and present in bacteria, mitochondria and chloroplasts, but its functional role in the cell remains unknown...
March 20, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28300532/mechanism-of-ribosome-rescue-by-arfa-and-rf2
#11
Gabriel Demo, Egor Svidritskiy, Rohini Madireddy, Ruben Diaz-Avalos, Timothy Grant, Nikolaus Grigorieff, Duncan Sousa, Andrei A Korostelev
ArfA rescues ribosomes stalled on truncated mRNAs by recruiting release factor RF2, which normally binds stop codons to catalyze peptide release. We report two 3.2 Å resolution cryo-EM structures - determined from a single sample - of the 70S ribosome with ArfA•RF2 in the A site. In both states, the ArfA C-terminus occupies the mRNA tunnel downstream of the A site. One state contains a compact inactive RF2 conformation. Ordering of the ArfA N-terminus in the second state rearranges RF2 into an extended conformation that docks the catalytic GGQ motif into the peptidyl-transferase center...
March 16, 2017: ELife
https://www.readbyqxmd.com/read/28298488/the-ribosome-bound-quality-control-complex-remains-associated-to-aberrant-peptides-during-their-proteasomal-targeting-and-interacts-with-tom1-to-limit-protein-aggregation
#12
Quentin Defenouillère, Abdelkader Namane, John Mouaikel, Alain Jacquier, Micheline Fromont-Racine
Protein quality control mechanisms eliminate defective polypeptides to ensure proteostasis and to avoid the toxicity of protein aggregates. In eukaryotes, the Ribosome-bound Quality Control (RQC) complex detects aberrant nascent peptides that remain stalled in 60S ribosomal particles due to a dysfunction in translation termination. The RQC complex polyubiquitylates aberrant polypeptides and recruits a Cdc48 hexamer to extract them from 60S particles in order to escort them to the proteasome for degradation...
March 15, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28258550/chemical-shift-assignments-of-ribosomal-protein-s1-from-mycobacterium-tuberculosis
#13
Jinglin Fu, Biling Huang, Donghai Lin, Xinli Liao
RpsA, also known as ribosomal protein S1, is an essential protein required for translation initiation of mRNAs when their Shine-Dalgarno sequence is degenerated (Sorensen et al. 1998). In addition, RpsA of Mycobacterium tuberculosis (M. tb) is involved in trans-translation, which is an effective system mediated by tmRNA-SmpB to release stalled ribosomes from mRNA in the presence of rare codons (Keiler 2008). Shi et al. found that POA binds to RpsA of Mtb and disrupts the formation of RpsA-tmRNA complex (Shi et al...
March 4, 2017: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/28258549/backbone-and-side-chain-resonance-assignments-for-the-tmrna-binding-protein-smpb-from-mycobacterium-tuberculosis
#14
Juanjuan Yang, Yindi Liu, Zhao Liu, Chun Meng, Donghai Lin
Small protein B (SmpB) is an essential molecule in trans-translation which is a universal biological pathway for protein synthesis in bacteria. Trans-translation can release stalled ribosomes from defective mRNAs and target tag-protein fragments for degradation, and then restart protein synthesis. The SmpB-tmRNA complex coordinating with other components of the trans-translation system, plays vital roles in Mycobacterium tuberculosis under both stress conditions and non-replicating conditions. Thus, elucidation of molecular details and dynamic properties of the SmpB-tmRNA interaction is a crucial step towards effectively blocking trans-translation process to shorten the duration of tuberculosis treatment...
March 4, 2017: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/28223409/asc1-hel2-and-slh1-couple-translation-arrest-to-nascent-chain-degradation
#15
Cole Stone Sitron, Joseph Hun Park, Onn Brandman
Premature arrest of protein synthesis within the open reading frame elicits a protective response that degrades the incomplete nascent chain. In this response, arrested 80S ribosomes are split into their large and small subunits, allowing assembly of the Ribosome Quality control Complex (RQC), which targets nascent chains for degradation. How the cell recognizes arrested nascent chains among the vast pool of actively translating polypeptides is poorly understood. We systematically examined translation arrest and modification of nascent chains in Saccharomyces cerevisiae to characterize the steps that couple arrest to RQC targeting...
February 21, 2017: RNA
https://www.readbyqxmd.com/read/28202229/requirement-of-the-rna-binding-protein-smpb-during-intracellular-growth-of-listeria-monocytogenes
#16
Mobarak Abu Mraheil, Renate Frantz, Lisa Teubner, Heiko Wendt, Uwe Linne, Jessica Wingerath, Thomas Wirth, Trinad Chakraborty
Bacterial trans-translation is the main quality control mechanism employed to relieve stalled ribosomes. Trans-translation is mediated by the small protein B (SmpB) and transfer-mRNA (tmRNA) ribonucleoprotein complex, which interacts with translational complexes stalled at the 3' end of non-stop mRNAs to release the stalled ribosomes thereby targeting the nascent polypeptides and truncated mRNAs for degradation. The trans-translation system exists with a few exceptions in all bacteria. In the present study, we assessed the contribution of SmpB to the growth and virulence of Listeria monocytogenes, a human intracellular food-borne pathogen that colonizes host tissues to cause severe invasive infections...
April 2017: International Journal of Medical Microbiology: IJMM
https://www.readbyqxmd.com/read/28193672/translation-of-poly-a-tails-leads-to-precise-mrna-cleavage
#17
Nicholas R Guydosh, Rachel Green
Translation of poly(A) tails leads to mRNA cleavage but the mechanism and global pervasiveness of this "nonstop/no-go" decay process is not understood. Here we performed ribosome profiling (in a yeast strain lacking exosome function) of short 15-18 nt mRNA footprints to identify ribosomes stalled at 3' ends of mRNA decay intermediates. In this background, we found mRNA cleavage extending hundreds of nucleotides upstream of ribosome stalling in poly(A) and predominantly in one reading frame. These observations suggest that decay-triggering endonucleolytic cleavage is closely associated with the ribosome...
February 13, 2017: RNA
https://www.readbyqxmd.com/read/28181542/elongation-factor-p-restricts-salmonella-s-growth-by-controlling-translation-of-a-mg-2-transporter-gene-during-infection
#18
Eunna Choi, Soomin Choi, Daesil Nam, Shinae Park, Yoontak Han, Jung-Shin Lee, Eun-Jin Lee
When a ribosome translates mRNA sequences, the ribosome often stalls at certain codons because it is hard to translate. Consecutive proline codons are such examples that induce ribosome stalling and elongation factor P (EF-P) is required for the stalled ribosome to continue translation at those consecutive proline codons. We found that EF-P is required for translation of the mgtB gene encoding a Mg(2+) transporter in the mgtCBR virulence operon from the intracellular pathogen Salmonella enterica serovar Typhimurium...
February 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28138069/ribosome-pausing-arrest-and-rescue-in-bacteria-and-eukaryotes
#19
REVIEW
Allen R Buskirk, Rachel Green
Ribosomes translate genetic information into polypeptides in several basic steps: initiation, elongation, termination and recycling. When ribosomes are arrested during elongation or termination, the cell's capacity for protein synthesis is reduced. There are numerous quality control systems in place to distinguish between paused ribosomes that need some extra input to proceed and terminally stalled ribosomes that need to be rescued. Here, we discuss similarities and differences in the systems for resolution of pauses and rescue of arrested ribosomes in bacteria and eukaryotes, and how ribosome profiling has transformed our ability to decipher these molecular events...
March 19, 2017: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/28132843/znf598-and-rack1-regulate-mammalian-ribosome-associated-quality-control-function-by-mediating-regulatory-40s-ribosomal-ubiquitylation
#20
Elayanambi Sundaramoorthy, Marilyn Leonard, Raymond Mak, Jeffrey Liao, Amitkumar Fulzele, Eric J Bennett
Ribosomes that experience terminal stalls during translation are resolved by ribosome-associated quality control (QC) pathways that oversee mRNA and nascent chain destruction and recycle ribosomal subunits. The proximal factors that sense stalled ribosomes and initiate mammalian ribosome-associated QC events remain undefined. We demonstrate that the ZNF598 ubiquitin ligase and the 40S ribosomal protein RACK1 help to resolve poly(A)-induced stalled ribosomes. They accomplish this by regulating distinct and overlapping regulatory 40S ribosomal ubiquitylation events...
February 16, 2017: Molecular Cell
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