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

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

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Laboratorio de Interacciones Biomoleculares y Cáncer, Instituto de Física, Universidad Autónoma de San Luis Potosí, Av. Manuel Nava 6, Zona Universitaria, 78290, SLP, México.
Équipe Labellisée Ligue Contre le Cancer, INSERM UMRS1162, Institut de Génétique Moléculaire, Université Paris 7, IUH Hôpital St. Louis, Paris, 75010, France.
RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic.


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.


E3 ubiquitin ligase substrate specificity; HDM2; HDMX; allosteric interactions; p53

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