Mapping Degradation Signals and Pathways in a Eukaryotic N-terminome

Mol Cell. 2018 May 3;70(3):488-501.e5. doi: 10.1016/j.molcel.2018.03.033.


Most eukaryotic proteins are N-terminally acetylated. This modification can be recognized as a signal for selective protein degradation (degron) by the N-end rule pathways. However, the prevalence and specificity of such degrons in the proteome are unclear. Here, by systematically examining how protein turnover is affected by N-terminal sequences, we perform a comprehensive survey of degrons in the yeast N-terminome. We find that approximately 26% of nascent protein N termini encode cryptic degrons. These degrons exhibit high hydrophobicity and are frequently recognized by the E3 ubiquitin ligase Doa10, suggesting a role in protein quality control. In contrast, N-terminal acetylation rarely functions as a degron. Surprisingly, we identify two pathways where N-terminal acetylation has the opposite function and blocks protein degradation through the E3 ubiquitin ligase Ubr1. Our analysis highlights the complexity of N-terminal degrons and argues that hydrophobicity, not N-terminal acetylation, is the predominant feature of N-terminal degrons in nascent proteins.

Keywords: N-end rule; N-terminal acetylation; N-terminal methionine excision; N-terminal processing; deep sequencing; massively parallel protein turnover assays; multiplexed protein stability profiling; protein quality control; selective protein degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Amino Acid Sequence
  • Eukaryotic Cells / metabolism*
  • Fungal Proteins / metabolism*
  • Proteolysis
  • Proteome / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Yeasts / metabolism


  • Fungal Proteins
  • Proteome
  • Ubiquitin-Protein Ligases