Nature 462, 808-812 (10 December 2009) | doi:10.1038/nature08612; Received 6 July 2009; Accepted 26 October 2009

Paradox of mistranslation of serine for alanine caused by AlaRS recognition dilemma

Min Guo1, Yeeting E. Chong1, Ryan Shapiro1, Kirk Beebe1,2, Xiang-Lei Yang1 & Paul Schimmel1

  1. The Skaggs Institute for Chemical Biology and Department of Molecular Biology, The Scripps Research Institute, BCC-379, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
  2. Present address: Metabolon, Inc., 800 Capitola Drive, Suite 1, Durham, North Carolina 27713, USA.

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

Mistranslation arising from confusion of serine for alanine by alanyl-tRNA synthetases (AlaRSs) has profound functional consequences1, 2, 3. 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 Gly1, 2. One checkpoint is the AlaRS editing centre, and the other is from widely distributed AlaXps—free-standing, genome-encoded editing proteins that clear Ser-tRNAAla. 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 snapshots of adenylate formation for each amino acid. An inherent dilemma is posed by constraints of a structural design that pins down the α-amino group of the bound amino acid by using an acidic residue. This design, dating back more than 3 billion years, creates a serendipitous interaction with the serine OH that is difficult to avoid. Apparently because no better architecture for the recognition of alanine could be found, the serine misactivation problem was solved through free-standing AlaXps, which appeared contemporaneously with early AlaRSs. The results reveal unconventional problems and solutions arising from the historical design of the protein synthesis machinery.