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Allosteric Interactions by p53 mRNA Govern HDM2 E3 Ubiquitin Ligase Specificity under Different Conditions.

Authors
  • Medina-Medina, Ixaura
  • García-Beltrán, Paola
  • de la Mora-de la Mora, Ignacio
  • Oria-Hernández, Jesús
  • Millot, Guy
  • Robin Fahraeus
  • Reyes-Vivas, Horacio
  • Sampedro, José G
  • Olivares-Illana, Vanesa
Type
Published Article
Journal
Molecular and Cellular Biology
Publisher
American Society for Microbiology
Publication Date
May 09, 2016
Volume
36
Issue
16
Pages
2195–2205
Identifiers
DOI: 10.1128/MCB.00113-16
PMID: 27215386
PMCID: PMC4968209
Source
USPC - SET - SVS
License
Green

Abstract

HDM2 and HDMX are key negative regulatory factors of the p53 tumor suppressor under normal conditions by promoting its degradation or preventing its trans activity, respectively. It has more recently been shown that both proteins can also act as positive regulators of p53 after DNA damage. This involves phosphorylation by ATM on serine residues HDM2(S395) and HDMX(S403), promoting their respective interaction with the p53 mRNA. However, the underlying molecular mechanisms of how these phosphorylation events switch HDM2 and HDMX from negative to positive regulators of p53 is not known. Our results show that these phosphorylation events reside within intrinsically disordered domains and change the conformation of the proteins. The modifications promote the exposition of N-terminal interfaces that support the formation of a new HDMX-HDM2 heterodimer independent of the C-terminal RING-RING interaction. The E3 ubiquitin ligase activity of this complex toward p53 is prevented by the p53 mRNA ligand but, interestingly, does not affect the capacity to ubiquitinate HDMX and HDM2. These results show how ATM-mediated modifications of HDMX and HDM2 switch HDM2 E3 ubiquitin ligase activity away from p53 but toward HDMX and itself and illustrate how the substrate specificity of HDM2 E3 ligase activity is regulated.

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