The majority of tRNA studies has focused on tRNA molecules as pivotal player in the fundamental
process of protein synthesis. Mounting studies have unveiled further functions for tRNA beyond
protein synthesis, including non-ribosomal amino acid transfer, and regulation of targeted proteolysis.
Post-translational N-terminal arginylation of protein fragments, a non-ribosomal amino acid transfer,
is one of the crucial ways by which tRNA participates in various protein degradation trajectories and
influences global cellular functions. Previous studies demonstrated a role of arginylation by arginyltransferases
(ATEs) in protein degradation, autophagy, and cell death in mammalian cells. Notably, recent
investigations in plants have revealed some of the crucial aspects regarding the biochemical nature of Nterminal
arginylation and some of its physiological roles. Herein, we review some of the key data on Nterminal
arginylation of protein fragments with respect to targeted proteolysis in mammalian cells. Future
mechanistic studies using state of the art approaches and physiologically-relevant cellular models are
warranted to enhance our molecular understanding of this important yet enigmatic protein modification.
Keywords: N-end rule, N-terminal arginylation, protein degradation, protein stability, protein turnover, proteolysis, ubiquitination.
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