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Allosteric changes in HDM2 by the ATM phosphomimetic S395D mutation: implications on HDM2 function
Lukas Uhrik1, Lixiao Wang2, Lucia Haronikova1
1Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty Kopec 7, 656 53 Brno, Czech Republic.
The Biochemical Journal
|October 26, 2019
Summary
Post-translational modifications alter protein functions. This study reveals how HDM2 protein structure changes regulate its interaction with p53, impacting cancer cell processes.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Proteins with intrinsic disorder regions undergo allosteric changes via post-translational modifications, regulating their functions.
- HDM2 is a key protein regulating the p53 tumor suppressor, switching between degradation and translation promotion.
- This switch is controlled by ataxia telangiectasia mutated (ATM) kinase phosphorylation at serine 395.
Purpose of the Study:
- To investigate the structural changes in HDM2 associated with its functional switch.
- To understand how these structural changes affect the HDM2 interactome, particularly its interaction with p53.
- To provide insights into the regulation of HDM2's role in p53 modulation and identify potential drug targets.
Main Methods:
- Utilized various biochemical and biophysical approaches.
- Investigated structural changes in HDM2.
- Analyzed alterations in the HDM2 interactome, including HDM2-p53 interactions.
Main Results:
- Demonstrated a specific structural change in HDM2 upon phosphorylation at serine 395 (or its mimic S395D).
- Showed that this structural alteration impacts the HDM2 interactome.
- Identified changes in the N-termini HDM2-p53 protein-protein interaction.
Conclusions:
- HDM2 undergoes specific structural changes that dictate its function as a regulator of p53.
- These findings enhance understanding of how HDM2 switches between inhibiting and promoting p53.
- The study highlights potential therapeutic targets at the interfaces of HDM2 interactions.
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