Role of RNA backbone groups for ribosomal catalysis

The ribosomal peptidyl transferase ribozyme resides in the large ribosomal subunit and catalyzes the two principal chemical reactions of protein synthesis, peptide bond formation and peptidyl-tRNA hydrolysis. With the presentations of atomic structures of the large ribosomal subunit, the questions how an RNA active site can catalyze these chemical reactions gained a new level of molecular significance. The peptidyl transferase center represents the most intense accumulation of universally conserved ribosomal RNA nucleotides in the entire ribosome. Thus, it came as a surprise that recent findings revealed that the nucleobase identities of active site residues are actually not critical for catalysis. Instead RNA backbone groups have been identified as key players in transpeptidation and peptide release. While the ribose 2’-OH of the 23S rRNA residue A2451 plays an important role in peptidyl transfer, its contribution to peptidyl-tRNA hydrolysis is only minor. On the other hand, the ribose 2’-OH of the terminal adenosine of P-site bound tRNA seems to play equally crucial roles in peptide bond formation and tRNA hydrolysis. While it seems that details of ribosome-catalyzed peptidyl-tRNA hydrolysis are just emerging, our molecular insights into transpeptidation are already very advanced. It has been realized that an intricate interaction between the ribose 2’-OH groups of 23S rRNA residue A2451 and tRNA nucleotide A76 is crucial for proton shuttling that is required for efficient amide bond synthesis.