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https://www.readbyqxmd.com/read/28528489/the-ribosome-bound-quality-control-complex-from-aberrant-peptide-clearance-to-proteostasis-maintenance
#1
REVIEW
Quentin Defenouillère, Micheline Fromont-Racine
Proteostasis in eukaryotes is maintained by compartment-specific quality control pathways, which enable the refolding or the degradation of defective polypeptides to prevent the toxicity that may arise from their aggregation. Among these processes, translational protein quality control is performed by the Ribosome-bound Quality Control complex (RQC), which recognizes nascent peptides translated from aberrant mRNAs, polyubiquitylates these aberrant peptides, extracts them from the stalled 60S subunit and finally escorts them to the proteasome for degradation...
May 20, 2017: Current Genetics
https://www.readbyqxmd.com/read/28525745/conditional-switch-between-frameshifting-regimes-upon-translation-of-dnax-mrna
#2
Neva Caliskan, Ingo Wohlgemuth, Natalia Korniy, Michael Pearson, Frank Peske, Marina V Rodnina
Ribosome frameshifting during translation of bacterial dnaX can proceed via different routes, generating a variety of distinct polypeptides. Using kinetic experiments, we show that -1 frameshifting predominantly occurs during translocation of two tRNAs bound to the slippery sequence codons. This pathway depends on a stem-loop mRNA structure downstream of the slippery sequence and operates when aminoacyl-tRNAs are abundant. However, when aminoacyl-tRNAs are in short supply, the ribosome switches to an alternative frameshifting pathway that is independent of a stem-loop...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28525744/ctf4-prevents-genome-rearrangements-by-suppressing-dna-double-strand-break-formation-and-its-end-resection-at-arrested-replication-forks
#3
Mariko Sasaki, Takehiko Kobayashi
Arrested replication forks lead to DNA double-strand breaks (DSBs), which are a major source of genome rearrangements. Yet DSB repair in the context of broken forks remains poorly understood. Here we demonstrate that DSBs that are formed at arrested forks in the budding yeast ribosomal RNA gene (rDNA) locus are normally repaired by pathways dependent on the Mre11-Rad50-Xrs2 complex but independent of HR. HR is also dispensable for DSB repair at stalled forks at tRNA genes. In contrast, in cells lacking the core replisome component Ctf4, DSBs are formed more frequently, and these DSBs undergo end resection and HR-mediated repair that is prone to rDNA hyper-amplification; this highlights Ctf4 as a key regulator of DSB end resection at arrested forks...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28522328/inhibiting-translation-one-protein-at-a-time
#4
Matthew D Disney
Historically, translational inhibitors have been confined to anti-bacterials that globally affect translation. Lintner et al. demonstrate that small molecules can specifically inhibit translation of a single disease-associated protein by stalling the ribosome's nascent chain [1], opening up a new therapeutic strategy for 'undruggable' proteins.
May 15, 2017: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/28507157/translation-and-folding-of-single-proteins-in-real-time
#5
Florian Wruck, Alexandros Katranidis, Knud H Nierhaus, Georg Büldt, Martin Hegner
Protein biosynthesis is inherently coupled to cotranslational protein folding. Folding of the nascent chain already occurs during synthesis and is mediated by spatial constraints imposed by the ribosomal exit tunnel as well as self-interactions. The polypeptide's vectorial emergence from the ribosomal tunnel establishes the possible folding pathways leading to its native tertiary structure. How cotranslational protein folding and the rate of synthesis are linked to a protein's amino acid sequence is still not well defined...
May 15, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28498106/kinetic-modeling-predicts-a-stimulatory-role-for-ribosome-collisions-at-elongation-stall-sites-in-bacteria
#6
Michael A Ferrin, Arvind R Subramaniam
Ribosome stalling on mRNAs can decrease protein expression. To decipher ribosome kinetics at stall sites, we induced ribosome stalling at specific codons by starving the bacterium Escherichia coli for the cognate amino acid. We measured protein synthesis rates from a reporter library of over 100 variants that encoded systematic perturbations of translation initiation rate, the number of stall sites, and the distance between stall sites. Our measurements are quantitatively inconsistent with two widely-used kinetic models for stalled ribosomes: ribosome traffic jams that block initiation, and abortive (premature) termination of stalled ribosomes...
May 12, 2017: ELife
https://www.readbyqxmd.com/read/28451135/resolving-the-%C3%AE-glycosidic-linkage-of-arginine-rhamnosylated-translation-elongation-factor-p-triggers-generation-of-the-first-arg-rha-specific-antibody
#7
Xiang Li, Ralph Krafczyk, Jakub Macošek, Yu-Lei Li, Yan Zou, Bernd Simon, Xing Pan, Qiu-Ye Wu, Fang Yan, Shan Li, Janosch Hennig, Kirsten Jung, Jürgen Lassak, Hong-Gang Hu
A previously discovered posttranslational modification strategy - arginine rhamnosylation - is essential for elongation factor P (EF-P) dependent rescue of polyproline stalled ribosomes in clinically relevant species such as Pseudomonas aeruginosa and Neisseria meningitidis. However, almost nothing is known about this new type of N-linked glycosylation. In the present study we used NMR spectroscopy to show for the first time that the α anomer of rhamnose is attached to Arg32 of EF-P, demonstrating that the corresponding glycosyltransferase EarP inverts the sugar of its cognate substrate dTDP-β-l-rhamnose...
December 1, 2016: Chemical Science
https://www.readbyqxmd.com/read/28436469/a-novel-method-to-evaluate-ribosomal-performance-in-cell-free-protein-synthesis-systems
#8
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
#9
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
#10
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...
May 2, 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
#11
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 25, 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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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...
May 1, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28258550/chemical-shift-assignments-of-ribosomal-protein-s1-from-mycobacterium-tuberculosis
#20
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
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