Thermodynamic control of −1 programmed ribosomal frameshifting

Bock, Lars V.; Caliskan, Neva; Korniy, Natalia; Peske, Frank; Rodnina, Marina V.; Grubmüller, Helmut

doi:10.1038/s41467-019-12648-x

Cited by 39 publications

(43 citation statements)

References 51 publications

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“…1). Mutations in the slippery sequence of dnaX were shown to decrease frameshifting efficiency to low ( 5%) or undetectable levels (Bock et al, 2019;Caliskan et al, 2017;Kim and Tinoco, 2017;Larsen et al, 1997;Tsuchihashi and Brown, 1992). The FSS from HIV also stalls the ribosome in the NR conformation.…”

Section: Resultsmentioning

confidence: 99%

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mRNA stem-loops can pause the ribosome by hindering A-site tRNA binding

Bao

Loerch

Ling

et al. 2020

Preprint

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Although the elongating ribosome is an efficient helicase, certain mRNA stem-loop structures are known to impede ribosome movement along mRNA and stimulate programmed ribosome frameshifting via mechanisms that are not well understood. Using biochemical and single-molecule Förster resonance energy transfer (smFRET) experiments, we studied how frameshift-inducing stem-loops from E. coli dnaX mRNA and the gag-pol transcript of Human Immunodeficiency Virus (HIV) perturb translation elongation. We find that upon encountering the ribosome, the stem-loops strongly inhibit A-site tRNA binding and ribosome intersubunit rotation that accompanies translation elongation. Electron cryo-microscopy (cryo-EM) reveals that the HIV stem-loop docks into the A site of the ribosome. Our results suggest that mRNA stem-loops can transiently escape ribosome helicase by binding to the A site. Thus, the stem-loops can modulate gene expression by sterically hindering tRNA binding and inhibiting translation elongation.

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Section: Resultsmentioning

confidence: 99%

“…The FSS is an RNA hairpin or a pseudoknot (Atkins et al, 2001). The slippery sequence allows cognate pairing of the P-site and A-site tRNAs in both 0 and -1 frames and thus makes frameshifting thermodynamically favorable (Bock et al, 2019). The mechanism by which FSS stimulates frameshifting is less clear.…”

Section: Introductionmentioning

confidence: 99%

mRNA stem-loops can pause the ribosome by hindering A-site tRNA binding

Bao

Loerch

Ling

et al. 2020

Preprint

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“…Since these studies have shown that in children with ASD the right parietal lobe deals with the processing of language content, this consequently implies difficulties in maintaining attention and emotional processing, since in children who develop normally these processes take place almost exclusively in the right hemisphere. Reduced degree of asymmetry in cerebral cortex thickness in a total of 1774 children with ASD compared with 1809 control peers from 54 independent data sources was confirmed for medial part of the frontal lobe, orbitofrontal cortex, cingulum and lower part of the parietal cortex [ 217 ].…”

Section: Autism Spectrum Disorder (Asd)mentioning

confidence: 99%

Molecules, Mechanisms, and Disorders of Self-Domestication: Keys for Understanding Emotional and Social Communication from an Evolutionary Perspective

et al. 2020

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The neural crest hypothesis states that the phenotypic features of the domestication syndrome are due to a reduced number or disruption of neural crest cells (NCCs) migration, as these cells differentiate at their final destinations and proliferate into different tissues whose activity is reduced by domestication. Comparing the phenotypic characteristics of modern and prehistoric man, it is clear that during their recent evolutionary past, humans also went through a process of self-domestication with a simultaneous prolongation of the period of socialization. This has led to the development of social abilities and skills, especially language, as well as neoteny. Disorders of neural crest cell development and migration lead to many different conditions such as Waardenburg syndrome, Hirschsprung disease, fetal alcohol syndrome, DiGeorge and Treacher-Collins syndrome, for which the mechanisms are already relatively well-known. However, for others, such as Williams-Beuren syndrome and schizophrenia that have the characteristics of hyperdomestication, and autism spectrum disorders, and 7dupASD syndrome that have the characteristics of hypodomestication, much less is known. Thus, deciphering the biological determinants of disordered self-domestication has great potential for elucidating the normal and disturbed ontogenesis of humans, as well as for the understanding of evolution of mammals in general.

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“…[3][4][5][6][7] During this pause, the t-RNA that is annealed within the ribosomal P-site (and most often also the t-RNA in the A-site) 8 begin to sample alternative base pairing interactions that shift the reading frame of the ribosme. 9 Based on these mechanistic considerations, PRF is typically believed to be mediated at the level of RNA structure. Nevertheless, recent reports have also found that the efficiency of PRF can be tuned by a variety of regulatory proteins and/ or miRNA.…”

Section: Introductionmentioning

confidence: 99%

Cotranslational folding stimulates programmed ribosomal frameshifting in the alphavirus structural polyprotein

Harrington

Zimmer

Chamness

et al. 2020

Journal of Biological Chemistry

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Viruses maximize their genetic coding capacity through a variety of biochemical mechanisms, including programmed ribosomal frameshifting (PRF), which facilitates the production of multiple proteins from a single mRNA transcript. PRF is typically stimulated by structural elements within the mRNA that generate mechanical tension between the transcript and ribosome. However, in this work, we show that the forces generated by the cotranslational folding of the nascent polypeptide chain can also enhance PRF. Using an array of biochemical, cellular, and computational techniques, we first demonstrate that the Sindbis virus structural polyprotein forms two competing topological isomers during its biosynthesis at the ribosome-translocon complex. We then show that the formation of one of these topological isomers is linked to PRF. Coarse-grained molecular dynamics simulations reveal that the translocon-mediated membrane integration of a transmembrane domain upstream from the ribosomal slip site generates a force on the nascent polypeptide chain that scales with observed frameshifting. Together, our results indicate that cotranslational folding of this viral protein generates a tension that stimulates PRF. To our knowledge, this constitutes the first example in which the conformational state of the nascent polypeptide chain has been linked to PRF. These findings raise the possibility that, in addition to RNA-mediated translational recoding, a variety of cotranslational folding or binding events may also stimulate PRF.

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Thermodynamic control of −1 programmed ribosomal frameshifting

Cited by 39 publications

References 51 publications

mRNA stem-loops can pause the ribosome by hindering A-site tRNA binding

mRNA stem-loops can pause the ribosome by hindering A-site tRNA binding

Molecules, Mechanisms, and Disorders of Self-Domestication: Keys for Understanding Emotional and Social Communication from an Evolutionary Perspective

Cotranslational folding stimulates programmed ribosomal frameshifting in the alphavirus structural polyprotein

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