C. Hwang, Anna Shemorry, A. Varshavsky
Feb 19, 2010
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Influential Citations
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Science
Abstract
To Degrade or Not to Degrade Regulating the turnover of proteins within the cell is of fundamental importance to almost every physiological process. Hwang et al. (p. 973, published online 28 January; see the Perspective by Mogk and Bukau) now find that acetylated N-terminal methionine (Met) is a degradation signal. This degron is recognized by Saccharomyces cerevisiae Doa10, a transmembrane E3 ubiquitin ligase that resides in the endoplasmic reticulum and inner nuclear membrane. The removal of N-terminal Met by Met-aminopeptidases generates N-terminal residues that are often N-terminally acetylated. Doa10 selectively binds to the resulting N-degrons, which may represent the most prevalent class of cellular protein degradation signals. In vivo protein stoichiometries are regulated through N-terminally acetylated degrons. 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 alanine (Ala), valine (Val), serine (Ser), threonine (Thr), and cysteine (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. Using the yeast Saccharomyces cerevisiae, we found 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 are a prevalent class of degradation signals in cellular proteins.