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2'-O-methylation in mRNA disrupts tRNA decoding during translation elongation.

<div class='caption-title'>(a) Single-molecule experimental schematics. Fluorescently labeled pre-initiation complex is tethered to the surface of the ZMW well via biotinylated mRNA, and necessary translation factors are delivered in the beginning of the signal acquisition.</div>
<div class='caption-title'>(a) mRNA sequence used to test the effect of 2′-O-methylation on the Phe codon, and the expected sequence of events between translocation from the previous codon and the peptidyl transfer reaction on Phe codon using Phe-(Cy5)-tRNAPhe.</div>
<div class='caption-title'>(a) A representative trace from the 10 mM total Mg2+ experimental condition (AAmA codon) shows a time-lag between the initial tRNA binding and the ribosomal intersubunit rotation, which follows the peptidyl transfer reaction. tRNA samplings and rotation lags on the modified codon were observed in all 3 2′-O-methylated codons.</div>
Choi J, Indrisiunaite G, DeMirci H, Ieong KW, Wang J, Petrov A, Prabhakar A, Rechavi G, Dominissini D, He C, Ehrenberg M, Puglisi JD
OpenAccess logo Nat Struct Mol Biol 25 208-216 (2018)
Related entries: 5wnp, 5wnr, 5wns, 5wnt, 5wnu, 5wnv

Cited: 70 times
EuropePMC logo PMID: 29459784

Abstract

Chemical modifications of mRNA may regulate many aspects of mRNA processing and protein synthesis. Recently, 2'-O-methylation of nucleotides was identified as a frequent modification in translated regions of human mRNA, showing enrichment in codons for certain amino acids. Here, using single-molecule, bulk kinetics and structural methods, we show that 2'-O-methylation within coding regions of mRNA disrupts key steps in codon reading during cognate tRNA selection. Our results suggest that 2'-O-methylation sterically perturbs interactions of ribosomal-monitoring bases (G530, A1492 and A1493) with cognate codon-anticodon helices, thereby inhibiting downstream GTP hydrolysis by elongation factor Tu (EF-Tu) and A-site tRNA accommodation, leading to excessive rejection of cognate aminoacylated tRNAs in initial selection and proofreading. Our current and prior findings highlight how chemical modifications of mRNA tune the dynamics of protein synthesis at different steps of translation elongation.

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  1. 2'-O-methylation in mRNA disrupts tRNA decoding during translation elongation. Choi J, Indrisiunaite G, DeMirci H, Ieong KW, Wang J, Petrov A, Prabhakar A, Rechavi G, Dominissini D, He C, Ehrenberg M, Puglisi JD. Nat Struct Mol Biol 25 208-216 (2018)


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