Structural basis for DNA damage-induced phosphoregulation of MDM2 RING domain

Helge M. Magnussen, Syed F. Ahmed, Gary J. Sibbet, Ventzislava A. Hristova, Koji Nomura, Andreas K. Hock, Lewis J. Archibald, Andrew G. Jamieson, David Fushman, Karen H. Vousden, Allan M. Weissman, Danny T. Huang (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)
72 Downloads (Pure)


Phosphorylation of MDM2 by ATM upon DNA damage is an important mechanism for deregulating MDM2, thereby leading to p53 activation. ATM phosphorylates multiple residues near the RING domain of MDM2, but the underlying molecular basis for deregulation remains elusive. Here we show that Ser429 phosphorylation selectively enhances the ubiquitin ligase activity of MDM2 homodimer but not MDM2-MDMX heterodimer. A crystal structure of phospho-Ser429 (pS429)-MDM2 bound to E2–ubiquitin reveals a unique 310-helical feature present in MDM2 homodimer that allows pS429 to stabilize the closed E2–ubiquitin conformation and thereby enhancing ubiquitin transfer. In cells Ser429 phosphorylation increases MDM2 autoubiquitination and degradation upon DNA damage, whereas S429A substitution protects MDM2 from auto-degradation. Our results demonstrate that Ser429 phosphorylation serves as a switch to boost the activity of MDM2 homodimer and promote its self-destruction to enable rapid p53 stabilization and resolve a long-standing controversy surrounding MDM2 auto-degradation in response to DNA damage.

Original languageEnglish
Article number2094
Number of pages15
JournalNature Communications
Publication statusPublished - 29 Apr 2020


  • DNA damage response
  • Proteolysis
  • Structural biology
  • Ubiquitin ligases
  • X-ray crystallography

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy


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