engleski

IleRS editing primarily targets norvaline whose misincorporation is more toxic than of valine

Translational errors may induce loss of protein stability and function. They are partly prevented by the editing activity of aminoacyl-tRNA synthetases (aaRSs). Norvaline (Nva) and valine are two isoleucine surrogates with identical mass: Val is a proteinogenic beta-branched amino acid, while the linear Nva sporadically accumulates in cells, but is not normally incorporated to proteins. We showed that Nva and Val are equally good non-cognate substrates of the deacylation- defective IleRS, both in vitro and in vivo. Surprisingly, however, IleRS distinguishes between Nva and Val at the CP1 editing domain that hydrolyses Nva-tRNAIle faster than Val-tRNAIle. We further demonstrated that incorporation of Nva into proteome is more deleterious, although Nva is mistranslated with similar frequency to Val and largely at the same Ile positions. Comparison of Nva-tRNA editing by IleRS, LeuRS and ValRS suggests Nva editing was present in their common ancestor, prior to its duplication and divergence to three specialized enzymes. This raises an intriguing hypothesis that elimination of Nva, which may had been present in primordial proteins, likely drove the acquisition of the CP1 editing domain.

aminoacyl-tRNA synthetases, norvaline, translational fidelity, toxicity of mistranslation

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