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The C terminus of p53 binds the N-terminal domain of MDM2

Nature Structural & Molecular Biology volume 17, pages 982–989 (2010)Cite this article

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A Corrigendum to this article was published on 06 April 2011

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Abstract

The p53 tumor suppressor interacts with its negative regulator Mdm2 via the former's N-terminal region and core domain, yet the extreme p53 C-terminal region contains lysine residues ubiquitinated by Mdm2 and can bear post-translational modifications that inhibit Mdm2-p53 association. We show that the Mdm2-p53 interaction is decreased upon deletion, mutation or acetylation of the p53 C terminus. Mdm2 decreases the association of full-length but not C-terminally deleted p53 with a DNA target sequence in vitro and in cells. Further, using multiple approaches, we show that a peptide from the p53 C terminus directly binds the Mdm2 N terminus in vitro. We also show that p300-acetylated p53 inefficiently binds Mdm2 in vitro, and Nutlin-3 treatment induces C-terminal modification(s) of p53 in cells, explaining the low efficiency of Nutlin-3 in dissociating p53-MDM2 in vitro.

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Figure 1: Contribution of the p53 C terminus to formation of the p53–Mdm2 complex.
Figure 2: Analysis of the binding between the N terminus of Mdm2 and p53 CTD.
Figure 3: Cross-linking and MS experiments implicate the N-terminal portion of Mdm2 in binding to the p53 CTD.
Figure 4: The p53 C terminus is required for Mdm2 to inhibit p53 DNA binding in vitro and in cells.
Figure 5: Nutlin-3 inhibits Mdm2–p53 complex formation and leads to modification of the p53 C terminus.
Figure 6: Nutlin-3, p14ARF and Mdm2 siRNA induce C-terminal modifications of p53.
Figure 7: Proposed mechanism for the function of the p53 C terminus and its modifications in Mdm2 complex formation.

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  • 25 July 2010

    In the version of this article initially published online, the Acknowledgments section was incomplete. The error has been corrected for the print, PDF and HTML versions of this article.

  • 21 September 2010

    In the version of this article initially published, the error bars in figures 1, 2, 4 and 5 were not defined, and a formatting mistake occurred in Supplementary Figure 1a. The errors have been corrected in the PDF and HTML versions of this article.

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Acknowledgements

We are exceedingly grateful to E. Freulich for her expert technical assistance and members of the Prives laboratory for their helpful suggestions. This work was supported by grant CA58316 from the US National Institutes of Health to C.P. A.F. is supported by a starting grant from the European Research Council under the European Community's Seventh Framework Programme (FP7/2007-2013) / ERC Grant agreement n° 203413.

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Authors and Affiliations

  1. Department of Biological Sciences, Columbia University, New York, New York, USA

    Masha V Poyurovsky, Oleg Laptenko, Rachel Beckerman, Maria Lokshin, Andrew Zupnick, Lewis M Brown & Carol Prives

  2. Department of Structural Biology, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania, USA

    Jinwoo Ahn & In-Ja L Byeon

  3. Institute of Chemistry, Hebrew University of Jerusalem, Safra Campus, Givat Ram, Jerusalem, Israel.,

    Chen Katz, Ronen Gabizon & Assaf Friedler

  4. Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York, USA

    Melissa Mattia

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Contributions

M.V.P., A.F. and C.P. designed research; M.V.P., C.K., O.L., M.L., J.A., I.-J.L.B., R.G., M.M., A.Z. and L.M.B. performed research and analyzed data; M.V.P. and C.P. wrote the manuscript.

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Correspondence to Carol Prives.

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Poyurovsky, M., Katz, C., Laptenko, O. et al. The C terminus of p53 binds the N-terminal domain of MDM2. Nat Struct Mol Biol 17, 982–989 (2010). https://doi.org/10.1038/nsmb.1872

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