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Docking-dependent ubiquitination of the interferon regulatory factor-1 tumor suppressor protein by the ubiquitin ligase CHIP.

Characteristically for a regulatory protein, the IRF-1 tumor suppressor turns over rapidly with a half-life of between 20-40 min. This allows IRF-1 to reach new steady state protein levels swiftly in response to changing environmental conditions. Whereas CHIP (C terminus of Hsc70-interacting protein), appears to chaperone IRF-1 in unstressed cells, formation of a stable IRF-1·CHIP complex is seen under specific stress conditions. Complex formation, in heat- or heavy metal-treated cells, is accompanied by a decrease in IRF-1 steady state levels and an increase in IRF-1 ubiquitination. CHIP binds directly to an intrinsically disordered domain in the central region of IRF-1 (residues 106-140), and this site is sufficient to form a stable complex with CHIP in cells and to compete in trans with full-length IRF-1, leading to a reduction in its ubiquitination. The study reveals a complex relationship between CHIP and IRF-1 and highlights the role that direct binding or "docking" of CHIP to its substrate(s) can play in its mechanism of action as an E3 ligase.

Pubmed ID: 20947504

Authors

  • Narayan V
  • Pion E
  • Landré V
  • Müller P
  • Ball KL

Journal

The Journal of biological chemistry

Publication Data

January 7, 2011

Associated Grants

  • Agency: Cancer Research UK, Id: C377/A6355

Mesh Terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Cell Line, Tumor
  • HSP70 Heat-Shock Proteins
  • Heat-Shock Response
  • Humans
  • Interferon Regulatory Factor-1
  • Metals, Heavy
  • Molecular Sequence Data
  • Peptide Fragments
  • Protein Binding
  • Protein Structure, Tertiary
  • Tumor Suppressor Proteins
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligases
  • Ubiquitination