Recent Research Developments

Aminoacyl-tRNA synthetases (aaRSs) activate specific amino acids and synthesize aminoacyl-tRNAs, which are essential intermediates in protein synthesis. The high fidelity of this process must be ensured in order for cells to survive. In some cases, the amino acid binding pocket of an aaRS is unable to effectively discriminate among chemically and/or structurally related amino acid substrates. In these cases, the high likelihood of misactivation and misacylation of a noncognate amino acid requires an error correction mechanism. Therefore, to ensure the exquisite specificity required for protein synthesis, aaRSs have evolved editing or proofreading functions.

Prolyl-tRNA synthetases (ProRSs) from all three domains of life have been shown to misactivate alanine and cysteine. Although most bacterial ProRSs possess an amino acid editing domain that deacylates mischarged Ala-tRNA^Pro, editing of Cys-tRNA^Pro has not been demonstrated. It was recently shown that a ProRS paralog, the YbaK protein from Haemophilus influenzae, which is homologous to the ProRS editing domain, is capable of weakly deacylating Ala-tRNA^Pro (F. Wong, P. J. Beuning, C. Silvers and K. Musier-Forsyth (2003) J. Biol. Chem. 278, 52857). This function appears to be redundant with that of its corresponding ProRS, which contains a canonical bacterial editing domain. Recently, graduate student Songon An of the Musier-Forsyth lab tested the specificity of editing by H. influenzae YbaK and showed that it efficiently edits Cys-tRNA^Pro and that a conserved Lys residue is essential for this activity (S. An and K. Musier-Forysth, J. Biol. Chem., in press). These findings represent the first example of an editing domain paralog possessing altered specificity, and suggest that similar autonomous editing domains could act upon different mischarged tRNAs thus providing cells with enhanced proofreading potential. This work also suggests a novel mechanism of editing wherein a third sieve is used to clear Cys-tRNA^Pro in at least some organisms (see Figure).

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