6t4q Citations

Molecular mechanism of translational stalling by inhibitory codon combinations and poly(A) tracts.

EMBO J 39 e103365 (2020)
Related entries: 6t7i, 6t7t, 6t83

Cited: 72 times
EuropePMC logo PMID: 31858614

Abstract

Inhibitory codon pairs and poly(A) tracts within the translated mRNA cause ribosome stalling and reduce protein output. The molecular mechanisms that drive these stalling events, however, are still unknown. Here, we use a combination of in vitro biochemistry, ribosome profiling, and cryo-EM to define molecular mechanisms that lead to these ribosome stalls. First, we use an in vitro reconstituted yeast translation system to demonstrate that inhibitory codon pairs slow elongation rates which are partially rescued by increased tRNA concentration or by an artificial tRNA not dependent on wobble base-pairing. Ribosome profiling data extend these observations by revealing that paused ribosomes with empty A sites are enriched on these sequences. Cryo-EM structures of stalled ribosomes provide a structural explanation for the observed effects by showing decoding-incompatible conformations of mRNA in the A sites of all studied stall- and collision-inducing sequences. Interestingly, in the case of poly(A) tracts, the inhibitory conformation of the mRNA in the A site involves a nucleotide stacking array. Together, these data demonstrate a novel mRNA-induced mechanisms of translational stalling in eukaryotic ribosomes.

Articles - 6t4q mentioned but not cited (2)

  1. Structure of the bacterial ribosome at 2 Å resolution. Watson ZL, Ward FR, Méheust R, Ad O, Schepartz A, Banfield JF, Cate JH. Elife 9 e60482 (2020)
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Reviews citing this publication (18)

  1. Roles of mRNA poly(A) tails in regulation of eukaryotic gene expression. Passmore LA, Coller J. Nat Rev Mol Cell Biol 23 93-106 (2022)
  2. Ribosome states signal RNA quality control. D'Orazio KN, Green R. Mol Cell 81 1372-1383 (2021)
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  6. Structural Heterogeneities of the Ribosome: New Frontiers and Opportunities for Cryo-EM. Poitevin F, Kushner A, Li X, Dao Duc K. Molecules 25 E4262 (2020)
  7. Ribosome-associated quality control of membrane proteins at the endoplasmic reticulum. Phillips BP, Miller EA. J Cell Sci 133 jcs251983 (2020)
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  9. Mechanisms of Attenuation by Genetic Recoding of Viruses. Gonçalves-Carneiro D, Bieniasz PD. mBio 12 e02238-20 (2021)
  10. Codon optimality in cancer. Gillen SL, Waldron JA, Bushell M. Oncogene 40 6309-6320 (2021)
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  12. Adaptation of Translational Machinery in Malaria Parasites to Accommodate Translation of Poly-Adenosine Stretches Throughout Its Life Cycle. Erath J, Djuranovic S, Djuranovic SP. Front Microbiol 10 2823 (2019)
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  16. Control of mRNA fate by its encoded nascent polypeptide. Höpfler M, Hegde RS. Mol Cell 83 2840-2855 (2023)
  17. Recoding of Nonsense Mutation as a Pharmacological Strategy. Temaj G, Telkoparan-Akillilar P, Nuhii N, Chichiarelli S, Saha S, Saso L. Biomedicines 11 659 (2023)
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Articles citing this publication (52)