Impact of Ser17 phosphorylation on the conformational dynamics of the oncoprotein MDM2

Juan A. Bueren-Calabuig, Julien Michel (Lead / Corresponding author)

Research output: Contribution to journalArticle

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Abstract

MDM2 is an important oncoprotein that downregulates the activity of the tumor suppressor protein p53 via binding of its N-terminal domain to the p53 transactivation domain. The first 24 residues of the MDM2 N-terminal domain form an intrinsically disordered "lid" region that interconverts on a millisecond time scale between "open" and "closed" states in unliganded MDM2. While the former conformational state is expected to facilitate p53 binding, the latter competes in a pseudosubstrate manner with p53 for its binding site. Phosphorylation of serine 17 in the MDM2 lid region is thought to modulate the equilibrium between "open" and "closed" lid states, but contradictory findings on the favored lid conformational state upon phosphorylation have been reported. Here, the nature of the conformational states of MDM2 pSer17 and Ser17Asp variants was addressed by means of enhanced sampling molecular dynamics simulations. Detailed analyses of the computed lid conformational ensembles indicate that both lid variants stabilize a "closed" state, with respect to wild type. Nevertheless, the nature of the closed-state conformational ensembles differs significantly between the pSer17 and Ser17Asp variants. Thus, care should be applied in the interpretation of biochemical experiments that use phosphomimetic variants to model the effects of phosphorylation on the structure and dynamics of this disordered protein region.

Original languageEnglish
Pages (from-to)2500-2509
Number of pages10
JournalBiochemistry
Volume55
Issue number17
DOIs
Publication statusPublished - 3 May 2016

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Phosphorylation
Oncogene Proteins
Tumor Suppressor Protein p53
Molecular Dynamics Simulation
Serine
Transcriptional Activation
Molecular dynamics
Down-Regulation
Binding Sites
Sampling
Computer simulation
Proteins
Experiments

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Bueren-Calabuig, Juan A. ; Michel, Julien. / Impact of Ser17 phosphorylation on the conformational dynamics of the oncoprotein MDM2. In: Biochemistry. 2016 ; Vol. 55, No. 17. pp. 2500-2509.
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Impact of Ser17 phosphorylation on the conformational dynamics of the oncoprotein MDM2. / Bueren-Calabuig, Juan A.; Michel, Julien (Lead / Corresponding author).

In: Biochemistry, Vol. 55, No. 17, 03.05.2016, p. 2500-2509.

Research output: Contribution to journalArticle

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