NDLI: Regulation of the E3 ubiquitin ligase activity of MDM2 by an N-terminal pseudo-substrate motif

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Regulation of the E3 ubiquitin ligase activity of MDM2 by an N-terminal pseudo-substrate motif

Content Provider	Springer Nature Link
Author	Worrall, Erin G. Wawrzyw, Bartosz Worrall, Liam Walkinshaw, Malcolm Ball, Kathryn L. Hupp, Ted R.
Copyright Year	2009
Abstract	The tumor suppressor p53 has evolved a MDM2-dependent feedback loop that promotes p53 protein degradation through the ubiquitin–proteasome system. MDM2 is an E3-RING containing ubiquitin ligase that catalyzes p53 ubiquitination by a dual-site mechanism requiring ligand occupation of its N-terminal hydrophobic pocket, which then stabilizes MDM2 binding to the ubiquitination signal in the DNA-binding domain of p53. A unique pseudo-substrate motif or “lid” in MDM2 is adjacent to its N-terminal hydrophobic pocket, and we have evaluated the effects of the flexible lid on the dual-site ubiquitination reaction mechanism catalyzed by MDM2. Deletion of this pseudo-substrate motif promotes MDM2 protein thermoinstability, indicating that the site can function as a positive regulatory element. Phospho-mimetic mutation in the pseudo-substrate motif at codon 17 (MDM2$^{S17D}$) stabilizes the binding of MDM2 towards two distinct peptide docking sites within the p53 tetramer and enhances p53 ubiquitination. Molecular modeling orientates the phospho-mimetic pseudo-substrate motif in equilibrium over a charged surface patch on the MDM2 at Arg$^{97}$/Lys$^{98}$, and mutation of these residues to the MDM4 equivalent reverses the activating effect of the phospho-mimetic mutation on MDM2 function. These data highlight the ability of the pseudo-substrate motif to regulate the allosteric interaction between the N-terminal hydrophobic pocket of MDM2 and its central acidic domain, which stimulates the E3 ubiquitin ligase function of MDM2. This model of MDM2 regulation implicates an as yet undefined lid-kinase as a component of pro-oncogenic pathways that stimulate the E3 ubiquitin ligase function of MDM2 in cells.
Starting Page	113
Ending Page	129
Page Count	17
File Format	PDF
ISSN	18646158
Journal	Journal of Chemical Biology
Volume Number	2
Issue Number	3
e-ISSN	18646166
Language	English
Publisher	Springer-Verlag
Publisher Date	2009-05-16
Publisher Place	Berlin, Heidelberg
Access Restriction	Subscribed
Subject Keyword	MDM2 p53 Allostery Kinase Ubiquitination Biochemistry Pharmacology/Toxicology Cell Biology Biophysics/Biomedical Physics Physical Chemistry
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Biophysics

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