Dual-site regulation of MDM2 E3-ubiquitin ligase activity

Maura Wallace, Erin Worrall, Susanne Pettersson, Ted R Hupp, Kathryn L Ball

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

The control of p53 ubiquitination by MDM2 provides a model system to define how an E3-ligase functions on a conformationally flexible substrate. The mechanism of MDM2-mediated ubiquitination of p53 has been analyzed by deconstructing, in vitro, the MDM2-dependent ubiquitination reaction. Surprisingly, ligands binding to the hydrophobic cleft of MDM2 do not inhibit its E3-ligase function. However, peptides from within the DNA binding domain of p53 that bind the acid domain of MDM2 inhibit ubiquitination of p53, localizing a motif that harbors a key ubiquitination signal. The binding of ligands to the N-terminal hydrophobic cleft of MDM2 reactivates, in vitro and in vivo, MDM2-catalyzed ubiquitination of p53F19A, a mutant p53 normally refractory to MDM2-catalyzed ubiquitination. We propose a model in which the interaction between the p53-BOX-I domain and the N terminus of MDM2 promotes conformational changes in MDM2 that stabilize acid-domain interactions with a ubiquitination signal in the DNA binding domain of the p53 tetramer.
Original languageEnglish
Pages (from-to)251-63
Number of pages13
JournalMolecular Cell
Issue number2
Publication statusPublished - 21 Jul 2006

Keywords / Materials (for Non-textual outputs)

  • Amino Acid Sequence
  • Cells, Cultured
  • Ligands
  • Models, Biological
  • Molecular Sequence Data
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-mdm2
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p53
  • Ubiquitin-Protein Ligases


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