New research now explains how 'editing' defects occur1 during translation of a genetic code and influence the removal of certain amindo acids attached to tRNA. Understanding this underlying mechanism is important as such defects result in disease conditions including neurodegeneration.
Proofreading or editing mechanisms play a crucial role in the faithful flow of information as dictated by the genetic code. The process of 'editing' by aminoacyl-tRNA synthetases is an important step in the accurate translation of the genetic code that removes noncognate amino acids attached to tRNA. While editing, the cognate amino acids larger by a methyl group are generally rejected.
Using solution-based direct binding studies, NMR-heteronuclear single quantum coherence (HSQC) and isothermal titration calorimetry experiments, the researchers showed that the cognate substrate can bind to the editing pocket. High-resolution crystal structural analyses revealed the key for the mechanism– the amino acids are rejected on the basis of functional positioning of substrates rather than steric exclusion.
The researchers say a strategically positioned 'catalytic water' molecule is excluded to avoid hydrolysis of the cognate substrate using a 'RNA mediated substrate-assisted catalysis mechanism' at the editing site. The critical role of RNA in proofreading activity is a unique solution to the problem of cognate-noncognate selection mechanism.
The study opens up an interesting question on the fundamental mechanism of discrimination of cognate amino acids at the proofreading step.
