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Title: | Characterizing the protein–protein interaction between MDM2 and 14-3-3σ; proof of concept for small molecule stabilization |
Author: | Ward, Jake A. Romartínez-Alonso, Beatriz Kay, Danielle Bellamy-Carter, Jeddidiah Thurairajah, Bethany Basran, Jaswir Kwon, Hanna Leney, Aneika C. Macip, Salvador Roversi, Pietro Muskett, Frederick Wilson Doveston, Richard |
Citation: | Ward, J.A. [Jake A.], Romartinez Alonso, B. [Beatriz], Kay, D.F.[Danielle F.], Bellamy Carter, J. [Jeddidah], Thurairajah, B. [Bethany], Basran, J. [Jaswir], Kwon, H. [Hanna], Leney, A.C.[Aneika C.], Macip, S. [Salvador], Roversi, P. [Pietro], Muskett, F.W. [Frederick W.] & Doveston, R.G. [Richard G.]. (2024). Characterizing the protein-protein interaction between MDM2 and 14-3-3σ; proof of concept for small molecule stabilization. Journal of Biological Chemistry, 300(2), 1-13. doi: 10.1016/j.jbc.2024.105651 |
Abstract: | Mouse Double Minute 2 (MDM2) is a key negative regulator of the tumor suppressor protein p53. MDM2 overexpression occurs in many types of cancer and results in the suppression of WT p53. The 14-3-3 family of adaptor proteins are known to bind MDM2 and the 14-3-3σ isoform controls MDM2 cellular localization and stability to inhibit its activity. Therefore, small molecule stabilization of the 14-3-3σ/MDM2 protein–protein interaction (PPI) is a potential therapeutic strategy for the treatment of cancer. Here, we provide a detailed biophysical and structural characterization of the phosphorylation-dependent interaction between 14-3-3σ and peptides that mimic the 14-3-3 binding motifs within MDM2. The data show that di-phosphorylation of MDM2 at S166 and S186 is essential for high affinity 14-3-3 binding and that the binary complex formed involves one MDM2 di-phosphorylated peptide bound to a dimer of 14-3-3σ. However, the two phosphorylation sites do not simultaneously interact so as to bridge the 14-3-3 dimer in a ‘multivalent’ fashion. Instead, the two phosphorylated MDM2 motifs ‘rock’ between the two binding grooves of the dimer, which is unusual in the context of 14-3-3 proteins. In addition, we show that the 14-3-3σ–MDM2 interaction is amenable to small molecule stabilization. The natural product fusicoccin A forms a ternary complex with a 14-3-3σ dimer and an MDM2 di-phosphorylated peptide resulting in the stabilization of the 14-3-3σ/MDM2 PPI. This work serves as a proof-of-concept of the drugability of the 14-3-3/MDM2 PPI and paves the way toward the development of more selective and efficacious small molecule stabilizers. |
Keywords: | protein protein interaction 14-3-3 proteins MDM2 p53 molecular glue |
DOI: | https://doi.org/10.1016/j.jbc.2024.105651 |
Document type: | info:eu-repo/semantics/article |
Version: | info:eu-repo/semantics/publishedVersion |
Issue Date: | Feb-2024 |
Publication license: | http://creativecommons.org/licenses/by/3.0/es/ |
Appears in Collections: | Articles Articles cientÍfics |
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File | Description | Size | Format | |
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Ward_JBC_Characterizing.pdf | 3,24 MB | Adobe PDF | View/Open |
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