p53 promotes its own polyubiquitination by enhancing the HDM2 and HDMX interaction

Protein Sci. 2018 May;27(5):976-986. doi: 10.1002/pro.3405. Epub 2018 Mar 25.


HDM2 and HDMX are two homologs essential for controlling p53 tumor suppressor activity under normal conditions. Both proteins bind different sites on the p53 N-terminus, and while HDM2 has E3 ubiquitin ligase activity towards p53, HDMX does not. Nevertheless, HDMX is required for p53 polyubiquitination and degradation, but the underlying molecular mechanism remains unclear. Alone, HDMX and HDM2 interact via their respective C-terminal RING domains but here we show that the presence of p53 induces an N-terminal interface under normal cellular conditions. This results in an increase in HDM2-mediated p53 polyubiquitination and degradation. The HDM2 inhibitor Nutlin-3 binds the N-terminal p53 binding pocket and is sufficient to induce the HDM2-HDMX interaction, suggesting that the mechanism depends on allosteric changes that control the multiprotein complex formation. These results demonstrate an allosteric interchange between three different proteins (HDMX-HDM2-p53) and help to explain the molecular mechanisms of HDM2-inhibitory drugs.

Keywords: E3 ubiquitin ligase substrate specificity; HDM2; HDMX; allosteric interactions; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins
  • Cell Line
  • Humans
  • Imidazoles / pharmacology
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / metabolism*
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-mdm2 / deficiency
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin / chemistry
  • Ubiquitin / metabolism*
  • Ubiquitination


  • Cell Cycle Proteins
  • Imidazoles
  • MDM4 protein, human
  • Nuclear Proteins
  • Piperazines
  • Proto-Oncogene Proteins
  • Tumor Suppressor Protein p53
  • Ubiquitin
  • nutlin 3
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2