Repurposing tRNAs for nonsense suppression

Suki Albers, Bertrand Beckert, Marco C. Matthies, Chandra Sekhar Mandava, Raphael Schuster, Carolin Seuring, Maria Riedner, Suparna Sanyal, Andrew E. Torda, Daniel N. Wilson and Zoya Ignatova ()
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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

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24076-x

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