The retained N-terminal methionine (Met) residue of a nascent protein is often N-terminally acetylated (Nt-acetylated). Removal of N-terminal Met by Met-aminopeptidases frequently leads to Nt-acetylation of the resulting N-terminal Ala, Val, Ser, Thr and Cys residues. Although a majority of eukaryotic proteins, for example, more than 80% of human proteins, are cotranslationally Nt-acetylated, the function of this extensively studied modification is largely unknown. Here we found, using the yeast Saccharomyces cerevisiae, that the Nt-acetylated Met residue could act as a degradation signal (degron), targeted by the Doa10 ubiquitin ligase. Moreover, Doa10 also recognized the Nt-acetylated Ala, Val, Ser, Thr and Cys residues. Several examined proteins of diverse functions contained these N-terminal degrons, termed AcN-degrons, which comprise a prevalent class of degradation signals in cellular proteins.
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