Structure and Mechanism of Aminoacyl-tRNA-Protein L/F- and R-transferases

The aminoacyl-tRNA-protein transferases (also known as aa-transferases) are a class of enzymes that utilize a highly conserved GCN5-related N-acetyltransferase (GNAT) fold to catalyze the post-translational transfer of amino acids from an aminoacylated transfer RNA (tRNA) to an acceptor protein. The two most important subclasses of aa-transferases are the prokaryotic L/F-transferases and the eukaryotic R-transferases (ATE1s). Both subclasses were initially discovered as early as the 1960s, and both share an overlapping function linked to protein degradation: L/F-transferases are known to modify proteins that are ultimately targeted for degradation via the Clp proteolytic pathway, while R-transferases (ATE1s) are known to modify proteins that may be targeted for degradation by the ubiquitin proteasome system (UPS), although many non-degradative fates may also occur. While L/F-transferases have been minimally explored at the cellular level, the R-transferases (ATE1s) have had extensive studies linking them to critical cellular functions. Despite over a half a century passing since their discoveries, X-ray crystallographic and cryo-EM studies have only recently begun to shed light onto the mechanism of these enzymes. This review underscores the functional importance of L/F- and R-transferases (ATE1s) and highlights the recent structural developments in this field with a particular emphasis on the eukaryotic R-transferases (ATE1s). Additionally, this review draws on current structural information to synopsize proposed catalytic and regulatory mechanisms for these enzymes. Finally, this review highlights important structural and mechanistic knowledge gaps in aa-transferase function that should be addressed in order to target these important enzymes for future therapeutic developments.