Abstract
Posttranslational arginylation is critical for embryogenesis, cardiovascular development, and angiogenesis, but its molecular effects and the identity of proteins arginylated in vivo are largely unknown. Here we report a global analysis of this modification on the protein level and identification of 43 proteins arginylated in vivo on highly specific sites. Our data demonstrate that unlike previously believed, arginylation can occur on any N-terminally exposed residue likely defined by a structural recognition motif on the protein surface, and that it preferentially affects a number of physiological systems, including cytoskeleton and primary metabolic pathways. The results of our study suggest that protein arginylation is a general mechanism for regulation of protein structure and function and outline the potential role of protein arginylation in cell metabolism and embryonic development.
Highlights
Protein arginylation is an enigmatic posttranslational modification mediated by arginyl-tRNA-protein transferase (ATE1) that transfers arginine (Arg) from tRNA onto proteins [1]
In this study we report a systematic characterization of posstranslational protein arginylation and identification of 43 proteins arginylated in vivo in different mouse tissues
Our analysis shows that (1) arginylation can occur on almost any N-terminally exposed residue without an apparent bias; (2) arginylation occurs on a highly limited and conserved number of sites in each protein located on the surface of the assembled molecule, which suggests arginylation target recognition by the secondary or higher order structure; and (3) arginylation is functionally associated with proteins involved in cytoskeleton and primary metabolic pathways
Summary
Protein arginylation is an enigmatic posttranslational modification mediated by arginyl-tRNA-protein transferase (ATE1) that transfers arginine (Arg) from tRNA onto proteins [1]. Until recently it had been believed that arginylation can only occur on the exposed N-terminus of aspartic acid (Asp), glutamic acid (Glu), or cysteine (Cys); a single case of the addition of Arg onto the side chain of Glu has been recently identified in vivo [2]. It has been believed that the molecular function of arginylation is to induce degradation of the target protein substrates by the ubiquitin-dependent N-end rule pathway [6]. Arginylation by ATE1 induces rapid degradation of experimentally constructed test proteins in yeast [6], and the half-life of RGS family proteins in mammals has been shown to decrease upon arginylation [7]. It has been found that arginylation regulates structure and intracellular assembly of beta actin in motile cells without affecting its short-term metabolic stability [8], suggesting that the function of arginylation in vivo may be more complex
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