The editing mechanism of aminoacyl-tRNA synthetases operates by a hybrid ribozyme/protein catalyst

3 March 2010 (Wed), 13:30 am - 14:30 am

6F seminar room, Central Bldg., Sengen site

Dr. Yohsuke Hagiwara(萩原陽介氏)

Tsukuba Univ. (筑波大学数理物質科学研究科物理学専攻)

The editing mechanism of aminoacyl-tRNA synthetases operates by a hybrid ribozyme/protein catalyst

Aminoacyl-tRNA synthetases (aaRSs) are critical for the translational process, catalyzing the attachment of specific amino acids to their cognate tRNAs. To ensure formation of the correct aminoacyl-tRNA, and thereby enhance the reliability of translation, several aaRSs have an editing capability that hinders formation of mis-aminoacylated tRNAs. We investigated theoretically the mechanism of the editing reaction for a class I enzyme, leucyl-tRNA synthetase (LeuRS), complexed with a mis-aminoacylated tRNALeu, employing ab initio hybrid quantum mechanical/molecular mechanical (QM/MM) potentials with all-electron density functional theory for the part of the QM calculations, in conjunction with molecular dynamics simulations. It is shown that the water molecule that acts as the nucleophile in the editing reaction is activated by a 3'-hydroxyl group at the 3'-end of tRNALeu, and that the O2' atom of the leaving group of the substrate is capped by one of the water’s hydrogen atoms. Thus, it is shown that editing is a self-cleavage reaction of the tRNA and so it is the tRNA, and not the protein, that drives the reaction. The protein does, however, have an important stabilizing effect on some high-energy intermediates along the reaction path, which is more efficient than the ribozyme would be alone. This indicates that editing is achieved by a novel “hybrid ribozyme/protein catalyst”. Analysis of existing experimental data and additional modeling shows that this ribozymal mechanism appears to be widespread, occurring in the ribosome as well as in other aaRSs. It also suggests transitional forms that could have played an important role in the RNA world hypothesis for the origin of life.

Reference: J. Am.Chem. Soc., DOI: 10.1021/ja9095208.

Dr. Hiori Kino(木野日織）