Journal Article

PUBDB-2024-05817

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Repurposing tRNAs for nonsense suppression

Albers, S. ; Beckert, B. ; Matthies, M. C. ; Mandava, C. S. ; Schuster, R. ; Seuring, C.CFEL*CSSB*XFEL.EU* ; Riedner, M. ; Sanyal, S. ; Torda, A. E. ; Wilson, D. N. ; Ignatova, Z. (Corresponding author)

2021
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-021-24076-x  doi:10.3204/PUBDB-2024-05817

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.

Note: This research was supported by grants from the Deutsche Forschungsgemeinschaft IG73/14-2 (to Z.I.) and WI2381/6-1 (to D.N.W.)

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Contributing Institute(s):

1. CSSB-CF-CRYO (CSSB-CF-CRYO)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Experiment(s):

1. No specific instrument

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