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Repurposing tRNAs for nonsense suppression

Author

Listed:
  • Suki Albers

    (Institute of Biochemistry and Molecular Biology, University of Hamburg)

  • Bertrand Beckert

    (Institute of Biochemistry and Molecular Biology, University of Hamburg)

  • Marco C. Matthies

    (Center for Bioinformatics, University of Hamburg)

  • Chandra Sekhar Mandava

    (Uppsala University)

  • Raphael Schuster

    (Institute of Organic Chemistry, University of Hamburg)

  • Carolin Seuring

    (Center for Structural and Systems Biology)

  • Maria Riedner

    (Institute of Organic Chemistry, University of Hamburg)

  • Suparna Sanyal

    (Uppsala University)

  • Andrew E. Torda

    (Center for Bioinformatics, University of Hamburg)

  • Daniel N. Wilson

    (Institute of Biochemistry and Molecular Biology, University of Hamburg)

  • Zoya Ignatova

    (Institute of Biochemistry and Molecular Biology, University of Hamburg)

Abstract

Three stop codons (UAA, UAG and UGA) terminate protein synthesis and are almost exclusively recognized by release factors. Here, we design de novo transfer RNAs (tRNAs) that efficiently decode UGA stop codons in Escherichia coli. The tRNA designs harness various functionally conserved aspects of sense-codon decoding tRNAs. Optimization within the TΨC-stem to stabilize binding to the elongation factor, displays the most potent effect in enhancing suppression activity. We determine the structure of the ribosome in a complex with the designed tRNA bound to a UGA stop codon in the A site at 2.9 Å resolution. In the context of the suppressor tRNA, the conformation of the UGA codon resembles that of a sense-codon rather than when canonical translation termination release factors are bound, suggesting conformational flexibility of the stop codons dependent on the nature of the A-site ligand. The systematic analysis, combined with structural insights, provides a rationale for targeted repurposing of tRNAs to correct devastating nonsense mutations that introduce a premature stop codon.

Suggested Citation

  • Suki Albers & Bertrand Beckert & Marco C. Matthies & Chandra Sekhar Mandava & Raphael Schuster & Carolin Seuring & Maria Riedner & Suparna Sanyal & Andrew E. Torda & Daniel N. Wilson & Zoya Ignatova, 2021. "Repurposing tRNAs for nonsense suppression," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24076-x
    DOI: 10.1038/s41467-021-24076-x
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    Cited by:

    1. Nikhil Bharti & Leonardo Santos & Marcos Davyt & Stine Behrmann & Marie Eichholtz & Alejandro Jimenez-Sanchez & Jeong S. Hong & Andras Rab & Eric J. Sorscher & Suki Albers & Zoya Ignatova, 2024. "Translation velocity determines the efficacy of engineered suppressor tRNAs on pathogenic nonsense mutations," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    2. Maria Luisa Romero Romero & Jonas Poehls & Anastasiia Kirilenko & Doris Richter & Tobias Jumel & Anna Shevchenko & Agnes Toth-Petroczy, 2024. "Environment modulates protein heterogeneity through transcriptional and translational stop codon readthrough," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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