Mistranslation and its control by tRNA synthetases

Abstract

Aminoacyl tRNA synthetases are ancient proteins that interpret the genetic material in all life forms.They are thought to have appeared during the transition from the RNA world to the theatre of proteins.During translation, they establish the rules of the genetic code, whereby each amino acid isattached to a tRNA that is cognate to the amino acid. Mistranslation occurs when an amino acidis attached to the wrong tRNA and subsequently is misplaced in a nascent protein. Mistranslationcan be toxic to bacteria and mammalian cells, and can lead to heritable mutations. The great challengefor nature appears to be serine-for-alanine mistranslation, where even small amounts of thismistranslation cause severe neuropathologies in the mouse. To minimize serine-for-alanine mistranslation,powerful selective pressures developed to prevent mistranslation through a special editingactivity imbedded within alanyl-tRNA synthetases (AlaRSs). However, serine-for-alanine mistranslationis so challenging that a separate, genome-encoded fragment of the editing domain ofAlaRS is distributed throughout the Tree of Life to redundantly prevent serine-to-alanine mistranslation.Detailed X-ray structural and functional analysis shed light on why serine-for-alaninemistranslation is a universal problem, and on the selective pressures that engendered the appearanceof AlaXps at the base of the Tree of Life. © 2011 The Royal Society.