Posttranslational arginylation as a global biological regulator

Abstract

Posttranslational modifications constitute a major field of emerging biological significance as mounting evidence demonstrates their key role in multiple physiological processes. Following in the footsteps of protein phosphorylation studies, new modifications are being shown to regulate protein properties and functions in vivo. Among such modifications, an important role belongs to protein arginylation - posttranslational tRNA-mediated addition of arginine, to proteins by arginyltransferase, ATE1. Recent studies show that arginylation is essential for embryogenesis in many organisms and that it regulates such important processes as heart development, angiogenesis, and tissue morphogenesis in mammals. This review summarizes the key data in the protein arginylation field since its original discovery to date.

Fig. 1. Summary of the arginylation reaction

According to the conventional theory, Ate1 transfers Arg from tRNA onto the N-terminally exposed amino group of the acceptor protein, forming a peptide bond (circled on the bottom of the diagram). Recent finding also demonstrate an example of Arg addition to the side chain of the Glu residue of neurotensin (circled on the side of the diagram). If mediated by Ate1, this reaction constitutes an additional or alternative mechanism of protein arginylation.

Fig. 2. Biological processes regulated by arginylation

Ate1 forms different complexes in vivo with roles in various intracellular processes that occur in the cytosol, nucleus, and the extracellular space.

Fig. 3. Mouse Ate1 knockout phenotypes

Top two panels, complete deletion of Ate1 results in embryonic lethality at and after E12.5, with severe defects in cardiovascular development and angiogenesis (Kwon et al., 2002) (embryos shown at E12.5). Middle panel, deletion of Ate1 in Wnt1-expressing migratory neural crest cells results in perinatal lethality accompanied by general retardation and defects in craniofacial morphogenesis (Kurosaka et al., 2010) (pups shown at postnatal day P6). Bottom panel, deletion of Ate1 in premeiotic germ cells driven by Tek promoter results in early post-implantation lethality (littermate control and mutant embryos at E12.5 are shown in bottom and top rows, respectively) (Leu et al., 2009). Arrows in all panels indicate mutant phenotypes. Photos courtesy of N. A. Leu (University of Pennsylvania).

Fig. 4

Schematic representation of the major organogenic defects resulting from Ate1 knockout in mice.