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ribosome stall

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
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
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
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
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
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
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
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...
February 1, 2017: International Journal of Medical Microbiology: IJMM
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
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
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
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
Yoshifumi Hashimoto, Masaki Takahashi, Eri Sakota, Yoshikazu Nakamura
When translating mRNAs are cleaved in protein-coding regions, 5' fragments of mRNAs are detached from stop codons (i.e., nonstop mRNAs) and protected from 3'-5' exonucleases by ribosomes stalled at the 3' termini. It has been shown in yeast that the nonstop mRNA decay (NSD) machinery triggers nonstop mRNA degradation by removing stalled ribosomes in the artificial reporter mRNAs. However, it is not known well whether NSD is involved in the degradation of endogenous nonstop mRNAs in higher eukaryotes. In this work, we addressed the question of whether 5'-nonstop-mRNA fragments generated by siRNA cleavage or nonsense-mediated-mRNA decay (NMD) are degraded by the NSD pathway in Drosophila melanogaster cells by knocking down three NSD components, Pelota (a yeast Dom34 homolog), Hbs1 and ABCE1 (a ribosome-recycling factor)...
January 20, 2017: Biochemical and Biophysical Research Communications
Junho Cho, Anita Carr, Lisa Whitworth, Brent Johnson, Kevin Scott Wilson
When exposed to antibiotics, many bacteria respond by activating intracellular "toxin" proteins, which arrest cell growth and induce formation of persister cells that survive antibiotics. After antibiotics are removed, persisters can regrow by synthesizing "antitoxin" proteins that sequester toxin proteins. In E. coli, MazE antitoxin sequesters the activity of MazF toxin, which extensively cleaves cellular RNAs. Although the functions of MazEF proteins are well characterized, there is surprisingly little known about their effects on cell structure...
January 22, 2017: Microbiology
Fuxing Zeng, Yanbo Chen, Jonathan Remis, Mrinal Shekhar, James C Phillips, Emad Tajkhorshid, Hong Jin
Quality control mechanisms intervene appropriately when defective translation events occur, in order to preserve the integrity of protein synthesis. Rescue of ribosomes translating on messenger RNAs that lack stop codons is one of the co-translational quality control pathways. In many bacteria, ArfA recognizes stalled ribosomes and recruits the release factor RF2, which catalyses the termination of protein synthesis. Although an induced-fit mechanism of nonstop mRNA surveillance mediated by ArfA and RF2 has been reported, the molecular interaction between ArfA and RF2 in the ribosome that is responsible for the mechanism is unknown...
January 26, 2017: Nature
Szymon Juszkiewicz, Ramanujan S Hegde
Diverse cellular stressors have been observed to trigger site-specific ubiquitination on several ribosomal proteins. However, the ubiquitin ligases, biochemical consequences, and physiologic pathways linked to these modifications are not known. Here, we show in mammalian cells that the ubiquitin ligase ZNF598 is required for ribosomes to terminally stall during translation of poly(A) sequences. ZNF598-mediated stalling initiated the ribosome-associated quality control (RQC) pathway for degradation of nascent truncated proteins...
February 16, 2017: Molecular Cell
Lucas D Serdar, DaJuan L Whiteside, Kristian E Baker
Nonsense-mediated mRNA decay (NMD) represents a eukaryotic quality control pathway that recognizes and rapidly degrades transcripts harbouring nonsense mutations to limit accumulation of non-functional and potentially toxic truncated polypeptides. A critical component of the NMD machinery is UPF1, an RNA helicase whose ATPase activity is essential for NMD, but for which the precise function and site of action remain unclear. We provide evidence that ATP hydrolysis by UPF1 is required for efficient translation termination and ribosome release at a premature termination codon...
December 23, 2016: Nature Communications
Tarek Hilal, Hiroshi Yamamoto, Justus Loerke, Jörg Bürger, Thorsten Mielke, Christian M T Spahn
The surveillance of mRNA translation is imperative for homeostasis. Monitoring the integrity of the message is essential, as the translation of aberrant mRNAs leads to stalling of the translational machinery. During ribosomal rescue, arrested ribosomes are specifically recognized by the conserved eukaryotic proteins Dom34 and Hbs1, to initiate their recycling. Here we solve the structure of Dom34 and Hbs1 bound to a yeast ribosome programmed with a nonstop mRNA at 3.3 Å resolution using cryo-electron microscopy...
December 20, 2016: Nature Communications
Jorge P López-Alonso, Attilio Fabbretti, Tatsuya Kaminishi, Idoia Iturrioz, Letizia Brandi, David Gil-Carton, Claudio O Gualerzi, Paola Fucini, Sean R Connell
In bacteria, the start site and the reading frame of the messenger RNA are selected by the small ribosomal subunit (30S) when the start codon, typically an AUG, is decoded in the P-site by the initiator tRNA in a process guided and controlled by three initiation factors. This process can be efficiently inhibited by GE81112, a natural tetrapeptide antibiotic that is highly specific toward bacteria. Here GE81112 was used to stabilize the 30S pre-initiation complex and obtain its structure by cryo-electron microscopy...
December 15, 2016: Nucleic Acids Research
Valda Vinson
No abstract text is available yet for this article.
December 16, 2016: Science
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