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DC Field | Value | Language |
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dc.contributor.author | Ward, Jake A. | - |
dc.contributor.author | Romartínez-Alonso, Beatriz | - |
dc.contributor.author | Kay, Danielle | - |
dc.contributor.author | Bellamy-Carter, Jeddidiah | - |
dc.contributor.author | Thurairajah, Bethany | - |
dc.contributor.author | Basran, Jaswir | - |
dc.contributor.author | Kwon, Hanna | - |
dc.contributor.author | Leney, Aneika C. | - |
dc.contributor.author | Macip, Salvador | - |
dc.contributor.author | Roversi, Pietro | - |
dc.contributor.author | Muskett, Frederick Wilson | - |
dc.contributor.author | Doveston, Richard | - |
dc.date.accessioned | 2024-10-30T08:25:15Z | - |
dc.date.available | 2024-10-30T08:25:15Z | - |
dc.date.issued | 2024-02 | - |
dc.identifier.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 | - |
dc.identifier.issn | 0021-9258MIAR | - |
dc.identifier.uri | http://hdl.handle.net/10609/151447 | - |
dc.description.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. | en |
dc.format.mimetype | application/pdf | ca |
dc.language.iso | eng | ca |
dc.publisher | American Society for Biochemistry and Molecular Biology | ca |
dc.relation.ispartof | Journal of Biological Chemistry (JBC), 2024, 300(2) | ca |
dc.relation.uri | https://www.jbc.org/article/S0021-9258(24)00027-9/fulltext | - |
dc.rights | CC BY | - |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | - |
dc.subject | protein protein interaction | en |
dc.subject | 14-3-3 proteins | en |
dc.subject | MDM2 | en |
dc.subject | p53 | en |
dc.subject | molecular glue | en |
dc.title | Characterizing the protein–protein interaction between MDM2 and 14-3-3σ; proof of concept for small molecule stabilization | en |
dc.type | info:eu-repo/semantics/article | ca |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.doi | https://doi.org/10.1016/j.jbc.2024.105651 | - |
dc.gir.id | AR/0000011375 | - |
dc.relation.projectID | info:eu-repo/grantAgreement/EP/W015803/1 | - |
dc.relation.projectID | info:eu-repo/grantAgreement/BB/S019456/1 | - |
dc.relation.projectID | info:eu-repo/grantAgreement/BBSRC/BB/M01116X/1 | - |
dc.relation.projectID | info:eu-repo/grantAgreement/BB/M01116X/1 | - |
dc.relation.projectID | info:eu-repo/grantAgreement/BB/S019456/1 | - |
dc.type.version | info:eu-repo/semantics/publishedVersion | - |
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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