scholarly journals Accuracy mechanism of eukaryotic ribosome translocation

Nature ◽  
2021 ◽  
Author(s):  
Muminjon Djumagulov ◽  
Natalia Demeshkina ◽  
Lasse Jenner ◽  
Alexey Rozov ◽  
Marat Yusupov ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Elongation Factor ◽  
80S Ribosome ◽  
Reading Frame ◽  
Transfer Rnas ◽  
Elongation Factor 2 ◽  
Complex Process ◽  
Translation Accuracy

AbstractTranslation of the genetic code into proteins is realized through repetitions of synchronous translocation of messenger RNA (mRNA) and transfer RNAs (tRNA) through the ribosome. In eukaryotes translocation is ensured by elongation factor 2 (eEF2), which catalyses the process and actively contributes to its accuracy1. Although numerous studies point to critical roles for both the conserved eukaryotic posttranslational modification diphthamide in eEF2 and tRNA modifications in supporting the accuracy of translocation, detailed molecular mechanisms describing their specific functions are poorly understood. Here we report a high-resolution X-ray structure of the eukaryotic 80S ribosome in a translocation-intermediate state containing mRNA, naturally modified eEF2 and tRNAs. The crystal structure reveals a network of stabilization of codon–anticodon interactions involving diphthamide1 and the hypermodified nucleoside wybutosine at position 37 of phenylalanine tRNA, which is also known to enhance translation accuracy2. The model demonstrates how the decoding centre releases a codon–anticodon duplex, allowing its movement on the ribosome, and emphasizes the function of eEF2 as a ‘pawl’ defining the directionality of translocation3. This model suggests how eukaryote-specific elements of the 80S ribosome, eEF2 and tRNAs undergo large-scale molecular reorganizations to ensure maintenance of the mRNA reading frame during the complex process of translocation.

scholarly journals A recent intermezzo at the Ribosome Club

2017 ◽  
Vol 372 (1716) ◽  
pp. 20160185 ◽  
Author(s):  
Michael Y. Pavlov ◽  
Anders Liljas ◽  
Måns Ehrenberg
Keyword(s):  
Messenger Rna ◽  
Ternary Complex ◽  
Elongation Factor ◽  
Transfer Rna ◽  
Elongation Factor Tu ◽  
Transfer Rnas ◽  
30S Subunit ◽  
Translation Accuracy ◽  
Codon Selection ◽  
Two Sides

Two sets of ribosome structures have recently led to two different interpretations of what limits the accuracy of codon translation by transfer RNAs. In this review, inspired by this intermezzo at the Ribosome Club, we briefly discuss accuracy amplification by energy driven proofreading and its implementation in genetic code translation. We further discuss general ways by which the monitoring bases of 16S rRNA may enhance the ultimate accuracy ( d -values) and how the codon translation accuracy is reduced by the actions of Mg 2+ ions and the presence of error inducing aminoglycoside antibiotics. We demonstrate that complete freezing-in of cognate-like tautomeric states of ribosome-bound nucleotide bases in transfer RNA or messenger RNA is not compatible with recent experiments on initial codon selection by transfer RNA in ternary complex with elongation factor Tu and GTP. From these considerations, we suggest that the sets of 30S subunit structures from the Ramakrishnan group and 70S structures from the Yusupov/Yusupova group may, after all, reflect two sides of the same coin and how the structurally based intermezzo at the Ribosome Club may be resolved simply by taking the dynamic aspects of ribosome function into account. This article is part of the themed issue ‘Perspectives on the ribosome’.

The Role of the Eukaryotic Elongation Factor 2 (eEF2) Pathway in Neuronal Function

2020 ◽  
Author(s):  
Elham Taha ◽  
Kobi Rosenblum
Keyword(s):  
Synaptic Plasticity ◽  
Molecular Mechanisms ◽  
Neurological Diseases ◽  
Elongation Factor ◽  
Mrna Translation ◽  
Translation Regulation ◽  
Neuronal Function ◽  
Elongation Factor 2 ◽  
Eukaryotic Elongation Factor 2 ◽  
Eukaryotic Elongation Factor

In the brain, mRNA translation regulation plays a major role during different processes, including development, learning and memory, and synaptic plasticity. While the initiation phase of translation is considered to be the rate-limiting step, regulation of the elongation phase via the eukaryotic elongation factor 2 kinase (eEF2K) pathway is also pivotal for memory and synaptic plasticity consolidation. Understanding the molecular mechanisms underpinning memory and synaptic plasticity formation is invaluable for understanding basic mechanisms underlying cognitive function and the identification of effective targets for cognitive disorders. This chapter discusses the molecular function of the eEF2/eEF2K pathway in memory consolidation, synaptic plasticity, and neurological diseases. In addition, it describes possible new genetic tools that would be useful in determining the neuronal function of eEF2K in health and disease conditions.

scholarly journals Translation inhibitory elements from Hoxa3 and Hoxa11 mRNAs use uORFs for translation inhibition

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Fatima Alghoul ◽  
Schaeffer Laure ◽  
Gilbert Eriani ◽  
Franck Martin
Keyword(s):  
Molecular Mechanisms ◽  
Stop Codon ◽  
Mrna Translation ◽  
Upstream Open Reading Frame ◽  
Initiation Factor ◽  
Entry Site ◽  
80S Ribosome ◽  
Stem Loop ◽  
Reading Frame ◽  
Translation Inhibition

During embryogenesis, Hox mRNA translation is tightly regulated by a sophisticated molecular mechanism that combines two RNA regulons located in their 5’UTR. First, an internal ribosome entry site (IRES) enables cap-independent translation. The second regulon is a translation inhibitory element or TIE, which ensures concomitant cap-dependent translation inhibition. In this study, we deciphered the molecular mechanisms of mouse Hoxa3 and Hoxa11 TIEs. Both TIEs possess an upstream open reading frame (uORF) that is critical to inhibit cap-dependent translation. However, the molecular mechanisms used are different. In Hoxa3 TIE, we identify an uORF which inhibits cap-dependent translation and we show the requirement of the non-canonical initiation factor eIF2D for this process. The mode of action of Hoxa11 TIE is different, it also contains an uORF but it is a minimal uORF formed by an uAUG followed immediately by a stop codon, namely a ‘start-stop’. The ‘start-stop’ sequence is species-specific and in mice, is located upstream of a highly stable stem loop structure which stalls the 80S ribosome and thereby inhibits cap-dependent translation of Hoxa11 main ORF.

scholarly journals Translation Inhibitory Elements from Hox a3 and a11 mRNAs use uORFs for translation inhibition

2021 ◽  
Author(s):  
Fatima Alghoul ◽  
Laure Schaeffer ◽  
Gilbert Eriani ◽  
Franck Martin
Keyword(s):  
Molecular Mechanisms ◽  
Stop Codon ◽  
Mrna Translation ◽  
Upstream Open Reading Frame ◽  
Initiation Factor ◽  
Entry Site ◽  
80S Ribosome ◽  
Stem Loop ◽  
Reading Frame ◽  
Translation Inhibition

AbstractDuring embryogenesis, Hox mRNA translation is tightly regulated by a sophisticated molecular mechanism that combines two RNA regulons located in their 5’UTR. First, an Internal Ribosome Entry Site (IRES) enables cap-independent translation. The second regulon is a Translation Inhibitory Element or TIE, which ensures concomitant cap-dependent translation inhibition. In this study, we deciphered the molecular mechanisms of Hox a3 and a11 TIE elements. Both TIEs possess an upstream Open Reading Frame (uORF) that is critical to inhibit cap-dependent translation. However, the molecular mechanisms used are different. In TIE a3, we identify a uORF which inhibits cap-dependent translation and we show the requirement of the non-canonical initiation factor eIF2D for this process. The mode of action of TIE a11 is different, it also contains a uORF but it is a minimal uORF formed by an uAUG followed immediately by a stop codon, namely a ‘start-stop’. The a11 ‘start-stop’ sequence is located upstream of a highly stable stem loop structure which stalls the 80S ribosome and thereby inhibits cap-dependent translation of Hox a11 main ORF.

scholarly journals A glance at molecular mechanisms underlying cisplatin-induced nephrotoxicity and possible renoprotective strategies: a narrative review

2019 ◽  
Vol 28 (3) ◽  
pp. 292-9
Author(s):  
Bashar Adi Wahyu Pandhita ◽  
Deliana Nur Ihsani Rahmi ◽  
Nielda Kezia Sumbung ◽  
Bernardino Matthew Waworuntu ◽  
Regina Puspa Utami ◽  
...  
Keyword(s):  
Large Scale ◽  
Molecular Mechanisms ◽  
Defense Mechanism ◽  
Therapeutic Interventions ◽  
Cellular Damage ◽  
Small Scale ◽  
Renal Tubular Cells ◽  
Complex Process ◽  
Current Article ◽  
Renal Tubular

Cisplatin is a platinum-based drug that is usually used for the treatment of many carcinomas. However, it comes with several devastating side effects, including nephrotoxicity. Cisplatin toxicity is a very complex process, which is exacerbated by the accumulation of cisplatin in renal tubular cells via passive diffusion and transporter-mediated processes. Once cisplatin enters these cells, it induces the formation of reactive oxygen species that cause cellular damage, including DNA damage, inflammation, and eventually cell death. On a small scale, these damages can be mitigated by cellular antioxidant defense mechanism. However, on a large scale, such as in chemotherapy, this defense mechanism may fail, resulting in nephrotoxicity. The current article reviews the molecular mechanisms underlying cisplatin-induced nephrotoxicity and possible renoprotective strategies to determine novel therapeutic interventions for alleviating this toxicity.

scholarly journals Identification of Elongation Factor-2 as a Novel Regulator of Mitochondrial Fission

2021 ◽  
Author(s):  
Jinhwan Kim ◽  
Yan Cheng ◽  
Yanfeng Li ◽  
Yi Zhang ◽  
Ji Cheng ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Critical Role ◽  
Elongation Factor ◽  
Binding Motif ◽  
Gtpase Activity ◽  
Elongation Factor 2 ◽  
Gtp Binding ◽  
And Function

Abstract Mitochondria continuously undergo morphologically dynamic processes of fusion and fission to maintain their size, shape, amount, and function; yet the precise molecular mechanisms by which mitochondrial dynamics is regulated remain to be fully elucidated. Here, we report a previous unappreciated but critical role of eukaryotic elongation factor 2 (eEF2) in regulating mitochondrial fission. eEF2, a G-protein superfamily member encoded by EEF2 gene in human, has long been appreciated as a promoter of the GTP-dependent translocation of the ribosome during protein synthesis. We found unexpectedly in several types of cells that eEF2 was not only present in the cytosol but also in the mitochondria. Furthermore, we showed that mitochondrial length was significantly increased when the cells were subjected to silencing of eEF2 expression, suggesting a promotive role for eEF2 in the mitochondrial fission. Inversely, overexpression of eEF2 decreased mitochondrial length, suggesting an increase of mitochondrial fission. Inhibition of mitochondrial fission caused by eEF2 depletion was accompanied by alterations of cellular metabolism, as evidenced by a reduction of oxygen consumption and an increase of oxidative stress in the mitochondria. We further demonstrated that eEF2 and Drp1, a key driver of mitochondrial fission, co-localized at the mitochondria, as evidenced by microscopic observation, co-immunoprecipitation, and GST pulldown assay. Deletion of the GTP binding motif of eEF2 decreased its association with Drp1 and abrogated its effect on mitochondria fission. Moreover, we showed that wild-type eEF2 stimulated GTPase activity of Drp1, whereas deletion of the GTP binding site of eEF2 diminished its stimulatory effect on GTPase activity. This work not only reveals a previously unrecognized function of eEF2 (i.e., promoting mitochondrial fission), but also uncovers the interaction of eEF2 with Drp1 as a novel regulatory mechanism of the mitochondrial dynamics. Therefore, eEF2 warrants further exploration for its potential as a therapeutic target for the mitochondria-related diseases.

Structural Insights into the Role of Diphthamide on Elongation Factor 2 in mRNA Reading-Frame Maintenance

2018 ◽  
Vol 430 (17) ◽  
pp. 2677-2687 ◽  
Author(s):  
Simone Pellegrino ◽  
Natalia Demeshkina ◽  
Eder Mancera-Martinez ◽  
Sergey Melnikov ◽  
Angelita Simonetti ◽  
...  
Keyword(s):  
Elongation Factor ◽  
Reading Frame ◽  
Elongation Factor 2 ◽  
Structural Insights

Methods of Network Planning and Management when Implementing Territory Planning Projects

2019 ◽  
pp. 49-54
Keyword(s):  
Large Scale ◽  
Housing Stock ◽  
Network Planning ◽  
Network Models ◽  
Point Of View ◽  
Residential Areas ◽  
Basic Principles ◽  
Planning And Management ◽  
Planning Project ◽  
Complex Process

The success of the Program of housing stock renovation in Moscow depends on the efficiency of resource management. One of the main urban planning documents that determine the nature of the reorganization of residential areas included in the Program of renovation is the territory planning project. The implementation of the planning project is a complex process that has a time point of its beginning and end, and also includes a set of interdependent parallel-sequential activities. From an organizational point of view, it is convenient to use network planning and management methods for project implementation. These methods are based on the construction of network models, including its varieties – a Gantt chart. A special application has been developed to simulate the implementation of planning projects. The article describes the basic principles and elements of modeling. The list of the main implementation parameters of the Program of renovation obtained with the help of the developed software for modeling is presented. The variants of using the results obtained for a comprehensive analysis of the implementation of large-scale urban projects are proposed.

Sign in / Sign up

Export Citation Format

Share Document