biostudies-literatureGuo MNIGMS NIH HHS808-12https://www.ebi.ac.uk/biostudies/studies/S-EPMC2799227biostudies-literatureUnknown462(7274)Mistranslation arising from confusion of serine for alanine by alanyl-tRNA synthetases (AlaRSs) has profound functional consequences. Throughout evolution, two editing checkpoints prevent disease-causing mistranslation from confusing glycine or serine for alanine at the active site of AlaRS. In both bacteria and mice, Ser poses a bigger challenge than Gly. One checkpoint is the AlaRS editing centre, and the other is from widely distributed AlaXps-free-standing, genome-encoded editing proteins that clear Ser-tRNA(Ala). The paradox of misincorporating both a smaller (glycine) and a larger (serine) amino acid suggests a deep conflict for nature-designed AlaRS. Here we show the chemical basis for this conflict. Nine crystal structures, together with kinetic and mutational analysis, provided snNatureParadox of mistranslation of serine for alanine caused by AlaRS recognition dilemma.PMC2799227GM 15539R01 GM015539Guo MBeebe KShapiro RSchimmel PChong YEYang XLfalseParadox of mistranslation of serine for alanine caused by AlaRS recognition dilemma.Mistranslation arising from confusion of serine for alanine by alanyl-tRNA synthetases (AlaRSs) has profound functional consequences. Throughout evolution, two editing checkpoints prevent disease-causing mistranslation from confusing glycine or serine for alanine at the active site of AlaRS. In both bacteria and mice, Ser poses a bigger challenge than Gly. One checkpoint is the AlaRS editing centre, and the other is from widely distributed AlaXps-free-standing, genome-encoded editing proteins that clear Ser-tRNA(Ala). The paradox of misincorporating both a smaller (glycine) and a larger (serine) amino acid suggests a deep conflict for nature-designed AlaRS. Here we show the chemical basis for this conflict. Nine crystal structures, together with kinetic and mutational analysis, provided sn2009-01-01T00:00:00Z2009 Dec2026-05-02T05:43:21.79Z2019-03-26T22:34:02ZS-EPMC27992272001069010.1038/nature08612