1. Department of Molecular Biology and Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
2. These authors contributed equally to this work.

Correspondence to: Paul Schimmel¹ Correspondence and requests for materials should be addressed to P.S. (Email: schimmel@scripps.edu).

Abstract

Synthesis of proteins containing errors (mistranslation) is prevented by aminoacyl transfer RNA synthetases through their accurate aminoacylation of cognate tRNAs and their ability to correct occasional errors of aminoacylation by editing reactions^{1, 2, 3, 4, 5}. A principal source of mistranslation comes from mistaking glycine or serine for alanine, which can lead to serious cell and animal pathologies, including neurodegeneration³. A single specific GU base pair (G3U70) marks a tRNA for aminoacylation by alanyl-tRNA synthetase^{6, 7, 8, 9}. Mistranslation occurs when glycine or serine is joined to the G3U70-containing tRNAs, and is prevented by the editing activity that clears the mischarged amino acid. Previously it was assumed that the specificity for recognition of tRNA^Ala for editing was provided by the same structural determinants as used for aminoacylation. Here we show that the editing site of alanyl-tRNA synthetase, as an artificial recombinant fragment, targets mischarged tRNA^Ala using a structural motif unrelated to that for aminoacylation so that, remarkably, two motifs (one for aminoacylation and one for editing) in the same enzyme independently can provide determinants for tRNA^Ala recognition. The structural motif for editing is also found naturally in genome-encoded protein fragments that are widely distributed in evolution^{10, 11, 12}. These also recognize mischarged tRNA^Ala. Thus, through evolution, three different complexes with the same tRNA can guard against mistaking glycine or serine for alanine.

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