How EF-Tu can contribute to efficient proofreading of aa-tRNA by the ribosome

Noel, Jeffrey K.; Whitford, Paul C.

doi:10.1038/ncomms13314

Cited by 62 publications

(130 citation statements)

References 70 publications

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“…This is central to the fidelity of gene expression, where the overall accuracy depends sensitively on accommodation kinetics . In addition, previous simulations have shown that a static EF‐Tu molecule can confine aa‐tRNA motion and reduce the free‐energy barrier of accommodation . Here, we consider whether a dynamic, extended and disordered EF‐Tu molecule could also influence accommodation kinetics.…”

Section: Resultsmentioning

confidence: 99%

“…For example, kinetic and single‐molecule measurements have shown that EF‐Tu can undergo a conformational change before dissociating from the ribosome, and other single‐molecule FRET measurements suggest aa‐tRNA can sample partially‐accommodated configurations prior to EF‐Tu dissociation. With regards to theoretical analyses, simulations have shown that EF‐Tu may confine aa‐tRNA movement, which has the potential to modulate the free‐energy barrier for aa‐tRNA accommodation . Here, we aim to further characterize the relationship between EF‐Tu and aa‐tRNA dynamics by quantifying the accessibility of extended/disordered ensembles when EF‐Tu is partially associated with the ribosome.…”

Section: Resultsmentioning

confidence: 99%

“…aa‐tRNA kinetics can depend on the sequence of conformational changes in EF‐Tu. The first step of aa‐tRNA accommodation involves movement from the A, A/T configuration to the B, Elbow‐accommodated (EA) conformation . C, The free energy as a function of R elbow (distance between U60 of aa‐tRNA and U8 of P‐site tRNA), obtained with an all‐atom structure‐based model in which EF‐Tu is absent (data set described in Ref.…”

Section: Resultsmentioning

confidence: 99%

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Disorder guides domain rearrangement in elongation factor Tu

2018

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Elongation factor Tu (EF-Tu) is a three-domain protein that is responsible for delivering aminoacyl-tRNA (aa-tRNA) molecules to the ribosome. During the delivery process, EF-Tu undergoes a large-scale (~50Å) conformational transition that results in rearrangement of domain I, relative to the II/III superdomain. Despite the central role of EF-Tu during protein synthesis, little is known about the structural and energetic properties of this reordering process. To study the physical-chemical properties of domain motion, we constructed a multi-basin structure-based (i.e., Gō-like) model, with which we have simulated hundreds of spontaneous conformational rearrangements. By analyzing the statistical properties of these events, we show that EF-Tu is likely to adopt a disordered intermediate ensemble during this transition. We further show that this disordered intermediate will favor a specific sequence of conformational substeps when bound to the ribosome, and the disordered ensemble can influence the kinetics of the incoming aa-tRNA molecule. Overall, this study highlights the dynamic nature of EF-Tu by revealing a relationship between conformational disorder and biological function.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Disorder guides domain rearrangement in elongation factor Tu

2018

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“…For a definitive result, two ribosomal attributes stand out for investigation because they relate directly to ribosome activity, though can still be influenced by trans-factors [71]. These are the elongation and error rates of the ribosome (Figure 5C, 5D).…”

Section: Identifying Ribosome Heterogeneitymentioning

confidence: 99%

“…mRNA specificity represents a key area where ribosome specialization could play a role ( Figure 5B). However, the degree of association of an individual mRNA with specific ribosomes can be determined not only by increased affinity of specialized ribosomes for the mRNA but also by altered mRNA abundance, and translation initiation factors.For a definitive result, two ribosomal attributes stand out for investigation because they relate directly to ribosome activity, though can still be influenced by trans-factors [71]. These are the elongation and error rates of the ribosome (Figure 5C, 5D).…”

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confidence: 99%

Ribosome stoichiometry: from form to function.

Emmott

Jovanović

Slavov

2018

Preprint

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The existence of eukaryotic ribosomes with distinct ribosomal protein (RP) stoichiometry and regulatory roles in protein synthesis been speculated for over sixty years. Recent advances in mass spectrometry and high throughput analysis have begun to identify and characterize distinct ribosome stoichiometry in yeast or mammalian systems. In addition to RP stoichiometry, ribosomes play host to a vast array of protein modifications, effectively expanding the number of human RPs from 80 to many thousands of distinct proteoforms. Is it possible these proteoforms combine to function as a 'ribosome code' to tune protein synthesis? We outline the specific benefits that translational regulation by specialized ribosomes can offer and discuss the means and methodologies available to correlate and characterize RP stoichiometry with function. We highlight previous research with a focus on formulating hypotheses that can guide future experiments and crack the 'ribosome code'.Ribosomes, the cellular machinery of protein synthesis, are present at up to ten million copies per cell in mammals. Despite their abundance and the wide array of known modifications to both ribosomal proteins (RPs) and rRNA, study of the direct role of the ribosome in tuning cellular translation has until recently taken a back seat to posttranscriptional regulation at the level of translation initiation. The hypothesis that ribosomes actively regulate protein synthesis as part of normal development and physiology dates back to the 1950s [1]. In the ensuing decades, numerous albeit inconclusive, observations have supported this hypothesis, and a subset of those are shown in Figure 1, color-coded by the type of evidence.For many years, the dominant 'abundance' model of translational regulation by the ribosome suggested a limited role for ribosomes in translation regulation [2]. In this model, if ribosomes have different initiation affinity for different transcripts, a global decrease in the availability of free ribosomes selectively decreases the initiation rates of different transcripts to varying degrees [2]. This mechanism, recently reviewed by Mills and Green [4], relies on the non-linear dependence of translation initiation on free ribosomes and applies quite generally. Indeed, recent research from the Sankaran lab suggested this mechanisms could explain the failure of erythroid lineage commitment seen with Diamond-Blackfan anaemia [5] 2 by the abundance model is limited in magnitude by the changes of total ribosomal content and in flexibility since it provides unidirectional regulation for all proteins.The concept of ribosome specialization In the 'specialized' ribosome model, ribosomes do not possess constant structure or composition (Figure 2A, B), and instead exhibit altered stoichiometry of what were previously thought to represent 'core' ribosomal proteins (Figure 1) [7,8]. In this model, different ribosomal compositions are functional and have specific roles in translation. Specialized ribosomes could co-exist within cells, or between ...

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Translation machinery captured in motion

2023

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Translation accuracy is one of the most critical factors for protein synthesis. It is regulated by the ribosome and its dynamic behavior, along with translation factors that direct ribosome rearrangements to make translation a uniform process. Earlier structural studies of the ribosome complex with arrested translation factors laid the foundation for an understanding of ribosome dynamics and the translation process as such. Recent technological advances in time‐resolved and ensemble cryo‐EM have made it possible to study translation in real time at high resolution. These methods provided a detailed view of translation in bacteria for all three phases: initiation, elongation, and termination. In this review, we focus on translation factors (in some cases GTP activation) and their ability to monitor and respond to ribosome organization to enable efficient and accurate translation.This article is categorized under: Translation > Ribosome Structure/Function Translation > Mechanisms

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How EF-Tu can contribute to efficient proofreading of aa-tRNA by the ribosome

Cited by 62 publications

References 70 publications

Disorder guides domain rearrangement in elongation factor Tu

Disorder guides domain rearrangement in elongation factor Tu

Ribosome stoichiometry: from form to function.

Translation machinery captured in motion

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