The N-terminal methionine of cellular proteins as a degradation signal

Cell. 2014 Jan 16;156(1-2):158-69. doi: 10.1016/j.cell.2013.11.031. Epub 2013 Dec 19.

Abstract

The Arg/N-end rule pathway targets for degradation proteins that bear specific unacetylated N-terminal residues while the Ac/N-end rule pathway targets proteins through their N(α)-terminally acetylated (Nt-acetylated) residues. Here, we show that Ubr1, the ubiquitin ligase of the Arg/N-end rule pathway, recognizes unacetylated N-terminal methionine if it is followed by a hydrophobic residue. This capability of Ubr1 expands the range of substrates that can be targeted for degradation by the Arg/N-end rule pathway because virtually all nascent cellular proteins bear N-terminal methionine. We identified Msn4, Sry1, Arl3, and Pre5 as examples of normal or misfolded proteins that can be destroyed through the recognition of their unacetylated N-terminal methionine. Inasmuch as proteins bearing the Nt-acetylated N-terminal methionine residue are substrates of the Ac/N-end rule pathway, the resulting complementarity of the Arg/N-end rule and Ac/N-end rule pathways enables the elimination of protein substrates regardless of acetylation state of N-terminal methionine in these substrates.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Metabolic Networks and Pathways
  • Methionine / metabolism*
  • Mice
  • Molecular Sequence Data
  • Protein Folding
  • Protein Sorting Signals*
  • Proteolysis*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / metabolism

Substances

  • Protein Sorting Signals
  • Saccharomyces cerevisiae Proteins
  • Methionine