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

Nature Structural & Molecular Biology
Masha V PoyurovskyCarol Prives

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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Sep 21, 2012·Journal of the American Chemical Society·Klaus MichelsenLeszek Poppe
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Methods Mentioned

BETA
NMR
pull-down
ubiquitination
enzyme-linked immunosorbent assay
ELISA
acetylates
footprinting
electrophoretic mobility shift assay
immunoprecipitation
acetylation

Software Mentioned

Mascot Wizard
Mascot

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