N-Terminal Acetylation of Cellular Proteins Creates Specific Degradation Signals

By C. Hwang, Anna Shemorry, A. Varshavsky. Science, 2010

634 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/e5cad02049a9d23a5943761b53cc46914ff06011

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Guido Kroemer
2. L. Galluzzi
3. Douglas R. Green
4. A. Varshavsky
5. Beth Levine
6. Simone Fulda
7. C. Brenner
8. Oliver Kepp

In Oncology

1. Guido Kroemer
2. L. Galluzzi
3. Douglas R. Green
4. A. Varshavsky

Citations in the corpus

• The N‐end rule pathway and regulation by proteolysis (2011, background): “are also in place (see The Ac/N-End Rule Pathway section), such proteins can become substrates of the Ac/N-end rule pathway.(3) [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.”
• High-throughput Analysis of in vivo Protein Stability* (2013, background): “Initiator methionines followed by a larger residue are often acetylated by other N-terminal acetyltransferases (e.g. NatB or NatC) depending on the property of the second residue (16, 17).”
• Metabolic control of cell death (2014, background): “N-terminal acetylation can promote protein degradation by theN-end rule pathway (75).”