−1 Programmed Ribosomal Frameshifting as a Force-Dependent Process

Visscher, Koen

doi:10.1016/bs.pmbts.2015.11.003

Cited by 5 publications

(5 citation statements)

References 118 publications

(166 reference statements)

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“…However, the nature of these tertiary interactions and the conformational dynamics of this frameshifting RNA element, including changes associated with 2A binding, are not well understood. For studying the thermodynamics and stability of these RNAs, the use of optical tweezers to conduct single-molecule force spectroscopy measurements can provide information beyond the resolution of conventional ensemble techniques, which are necessarily limited by molecular averaging 27 . In recent years, such approaches have yielded insights into various nucleic acid structures 28–31 and dynamic cellular processes 32,33 as well as mechanisms of PRF 16,34–36 .…”

Section: Introductionmentioning

confidence: 99%

“…However, the nature of these interactions and the conformational dynamics of this frameshifting RNA element, including changes associated with 2A binding, are not well understood. To better define the conformational landscape of such RNAs, observing the folding and unfolding trajectories of individual molecules under tension can provide information beyond the resolution of conventional ensemble techniques, which are necessarily limited by molecular averaging (Visscher, 2016). In recent years, the application of single molecule force spectroscopy as a tool for probing structural transitions has yielded unprecedented insights into various nucleic acid structures (Chandra et al, 2017; Greenleaf et al, 2008; Mandal et al, 2019; Yang et al, 2018; Zhong et al, 2016), dynamic cellular processes (Desai et al, 2019; Wen et al, 2008) as well as mechanisms of PRF (Chen et al, 2017; Green et al, 2008; Halma et al, 2019; Yan et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Structural and molecular basis for Cardiovirus 2A protein as a viral gene expression switch

Hill

Napthine

Pekarek

et al. 2020

Preprint

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Encephalomyocarditis virus 2A protein is a multi functional virulence factor essential for efficient virus replication with roles in stimulating programmed -1 ribosomal frameshifting (PRF), inhibiting cap-dependent translational initiation, interfering with nuclear import and export and preventing apoptosis of infected cells. The mechanistic basis for many of these activities is unclear and a lack of structural data has hampered our understanding. Here we present the X-ray crystal structure of 2A, revealing a novel 'beta-shell' fold. We show that 2A selectively binds to and stabilises a specific conformation of the stimulatory RNA element in the viral genome that directs PRF at the 2A/2B* junction. We dissect the folding energy landscape of this stimulatory RNA element, revealing multiple conformers, and measure changes in unfolding pathways arising from mutation and 2A binding. Furthermore, we demonstrate a strong interaction between 2A and the small ribosomal subunit and present a high-resolution cryo-EM structure of 2A bound to initiated 70S ribosomes. In this complex, three copies of 2A bind directly to 16S ribosomal RNA at the factor binding site, where they may compete for binding with initiation and elongation factors. Together, these results provide an integrated view of the structural basis for RNA recognition by 2A, expand our understanding of PRF, and provide unexpected insights into how a multifunctional viral protein may shut down translation during virus infection.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural and molecular basis for Cardiovirus 2A protein as a viral gene expression switch

Hill

Napthine

Pekarek

et al. 2020

Preprint

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“…For molecular motors, the force mechanics of the nucleic acid substrate can determine the subsequent mechanics of the molecular motor (Halma et al . 2019 ; Visscher 2016 ; Wuite et al . 2000 ).…”

Section: Force Ranges In Biologymentioning

confidence: 99%

Life under tension: the relevance of force on biological polymers

Halma,

2024

swwlxb

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Optical tweezers have elucidated numerous biological processes, particularly by enabling the precise manipulation and measurement of tension. One question concerns the biological relevance of these experiments and the generalizability of these experiments to wider biological systems. Here, we categorize the applicability of the information garnered from optical tweezers in two distinct categories: the direct relevance of tension in biological systems, and what experiments under tension can tell us about biological systems, while these systems do not reach the same tension as the experiment, still, these artificial experimental systems reveal insights into the operations of biological machines and life processes.

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“…Interestingly, the force generated by the ribosome to unfold temporary mRNA structures is comparable to the force required for the ribosome to overcome stalling along the mRNA transcript [29]. Ribosome pausing, whether through stalling or the presence of secondary mRNA structures, will not only regulate translation rates but also processes such as co-translational folding (see Section 2.3) and frameshifting [30].…”

Section: Mrna Secondary Structures As Mechanical Barriers To the Ribomentioning

confidence: 99%

Mechanical Forces and Their Effect on the Ribosome and Protein Translation Machinery

Simpson

Reader

Tzima

2020

Cells

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Mechanical forces acting on biological systems, at both the macroscopic and microscopic levels, play an important part in shaping cellular phenotypes. There is a growing realization that biomolecules that respond to force directly applied to them, or via mechano-sensitive signalling pathways, can produce profound changes to not only transcriptional pathways, but also in protein translation. Forces naturally occurring at the molecular level can impact the rate at which the bacterial ribosome translates messenger RNA (mRNA) transcripts and influence processes such as co-translational folding of a nascent protein as it exits the ribosome. In eukaryotes, force can also be transduced at the cellular level by the cytoskeleton, the cell's internal filamentous network. The cytoskeleton closely associates with components of the translational machinery such as ribosomes and elongation factors and, as such, is a crucial determinant of localized protein translation. In this review we will give (1) a brief overview of protein translation in bacteria and eukaryotes and then discuss (2) how mechanical forces are directly involved with ribosomes during active protein synthesis and (3) how eukaryotic ribosomes and other protein translation machinery intimately associates with the mechanosensitive cytoskeleton network.

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−1 Programmed Ribosomal Frameshifting as a Force-Dependent Process

Cited by 5 publications

References 118 publications

Structural and molecular basis for Cardiovirus 2A protein as a viral gene expression switch

Structural and molecular basis for Cardiovirus 2A protein as a viral gene expression switch

Life under tension: the relevance of force on biological polymers

Mechanical Forces and Their Effect on the Ribosome and Protein Translation Machinery

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