Proteomics Links Ubiquitin Chain Topology Change to Transcription Factor Activation

Mol Cell. 2019 Oct 3;76(1):126-137.e7. doi: 10.1016/j.molcel.2019.07.001. Epub 2019 Aug 20.


A surprising complexity of ubiquitin signaling has emerged with identification of different ubiquitin chain topologies. However, mechanisms of how the diverse ubiquitin codes control biological processes remain poorly understood. Here, we use quantitative whole-proteome mass spectrometry to identify yeast proteins that are regulated by lysine 11 (K11)-linked ubiquitin chains. The entire Met4 pathway, which links cell proliferation with sulfur amino acid metabolism, was significantly affected by K11 chains and selected for mechanistic studies. Previously, we demonstrated that a K48-linked ubiquitin chain represses the transcription factor Met4. Here, we show that efficient Met4 activation requires a K11-linked topology. Mechanistically, our results propose that the K48 chain binds to a topology-selective tandem ubiquitin binding region in Met4 and competes with binding of the basal transcription machinery to the same region. The change to K11-enriched chain architecture releases this competition and permits binding of the basal transcription complex to activate transcription.

Publication types

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

MeSH terms

  • Basic-Leucine Zipper Transcription Factors / chemistry
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Binding Sites
  • Binding, Competitive
  • Chromatography, Liquid
  • Gene Expression Regulation, Fungal
  • Lysine
  • Mutation
  • Protein Binding
  • Protein Conformation
  • Proteomics / methods*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Structure-Activity Relationship
  • Tandem Mass Spectrometry
  • Transcription, Genetic*
  • Transcriptional Activation*
  • Ubiquitination*


  • Basic-Leucine Zipper Transcription Factors
  • MET4 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Lysine