Adoption of a turn conformation drives the binding affinity of p53 C-terminal domain peptides to 14-3-3σ

Ave Kuusk, Joaõ Filipe Neves, Kenny Bravo-Rodriguez, Anders Gunnarsson, Yasser B. Ruiz-Blanco, Michael Ehrmann, Hongming Chen, Isabelle Landrieu (Corresponding author), Elsa Sanchez-Garcia (Corresponding author), Helen Boyd (Corresponding author), Christian Ottmann (Corresponding author), Richard G. Doveston (Corresponding author)

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Abstract

The interaction between the adapter protein 14-3-3σ and transcription factor p53 is important for preserving the tumor-suppressor functions of p53 in the cell. A phosphorylated motif within the C-terminal domain (CTD) of p53 is key for binding to the amphipathic groove of 14-3-3. This motif is unique among 14-3-3 binding partners, and the precise dynamics of the interaction is not yet fully understood. Here, we investigate this interaction at the molecular level by analyzing the binding of different length p53 CTD peptides to 14-3-3σ using ITC, SPR, NMR, and MD simulations. We observed that the propensity of the p53 peptide to adopt turn-like conformation plays an important role in the binding to the 14-3-3σ protein. Our study contributes to elucidate the molecular mechanism of the 14-3-3-p53 binding and provides useful insight into how conformation properties of a ligand influence protein binding.

Original languageEnglish
Pages (from-to)262-271
Number of pages10
JournalACS Chemical Biology
Volume15
Issue number1
DOIs
Publication statusPublished - 17 Jan 2020

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14-3-3 Proteins
Conformations
Peptides
Protein Binding
Tumors
Transcription Factors
Nuclear magnetic resonance
Ligands
Neoplasms
Protein Domains

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Kuusk, A., Neves, J. F., Bravo-Rodriguez, K., Gunnarsson, A., Ruiz-Blanco, Y. B., Ehrmann, M., ... Doveston, R. G. (2020). Adoption of a turn conformation drives the binding affinity of p53 C-terminal domain peptides to 14-3-3σ. ACS Chemical Biology, 15(1), 262-271. https://doi.org/10.1021/acschembio.9b00893
Kuusk, Ave ; Neves, Joaõ Filipe ; Bravo-Rodriguez, Kenny ; Gunnarsson, Anders ; Ruiz-Blanco, Yasser B. ; Ehrmann, Michael ; Chen, Hongming ; Landrieu, Isabelle ; Sanchez-Garcia, Elsa ; Boyd, Helen ; Ottmann, Christian ; Doveston, Richard G. / Adoption of a turn conformation drives the binding affinity of p53 C-terminal domain peptides to 14-3-3σ. In: ACS Chemical Biology. 2020 ; Vol. 15, No. 1. pp. 262-271.
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abstract = "The interaction between the adapter protein 14-3-3σ and transcription factor p53 is important for preserving the tumor-suppressor functions of p53 in the cell. A phosphorylated motif within the C-terminal domain (CTD) of p53 is key for binding to the amphipathic groove of 14-3-3. This motif is unique among 14-3-3 binding partners, and the precise dynamics of the interaction is not yet fully understood. Here, we investigate this interaction at the molecular level by analyzing the binding of different length p53 CTD peptides to 14-3-3σ using ITC, SPR, NMR, and MD simulations. We observed that the propensity of the p53 peptide to adopt turn-like conformation plays an important role in the binding to the 14-3-3σ protein. Our study contributes to elucidate the molecular mechanism of the 14-3-3-p53 binding and provides useful insight into how conformation properties of a ligand influence protein binding.",
author = "Ave Kuusk and Neves, {Joa{\~o} Filipe} and Kenny Bravo-Rodriguez and Anders Gunnarsson and Ruiz-Blanco, {Yasser B.} and Michael Ehrmann and Hongming Chen and Isabelle Landrieu and Elsa Sanchez-Garcia and Helen Boyd and Christian Ottmann and Doveston, {Richard G.}",
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Kuusk, A, Neves, JF, Bravo-Rodriguez, K, Gunnarsson, A, Ruiz-Blanco, YB, Ehrmann, M, Chen, H, Landrieu, I, Sanchez-Garcia, E, Boyd, H, Ottmann, C & Doveston, RG 2020, 'Adoption of a turn conformation drives the binding affinity of p53 C-terminal domain peptides to 14-3-3σ', ACS Chemical Biology, vol. 15, no. 1, pp. 262-271. https://doi.org/10.1021/acschembio.9b00893

Adoption of a turn conformation drives the binding affinity of p53 C-terminal domain peptides to 14-3-3σ. / Kuusk, Ave; Neves, Joaõ Filipe; Bravo-Rodriguez, Kenny; Gunnarsson, Anders; Ruiz-Blanco, Yasser B.; Ehrmann, Michael; Chen, Hongming; Landrieu, Isabelle (Corresponding author); Sanchez-Garcia, Elsa (Corresponding author); Boyd, Helen (Corresponding author); Ottmann, Christian (Corresponding author); Doveston, Richard G. (Corresponding author).

In: ACS Chemical Biology, Vol. 15, No. 1, 17.01.2020, p. 262-271.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Kuusk, Ave

AU - Neves, Joaõ Filipe

AU - Bravo-Rodriguez, Kenny

AU - Gunnarsson, Anders

AU - Ruiz-Blanco, Yasser B.

AU - Ehrmann, Michael

AU - Chen, Hongming

AU - Landrieu, Isabelle

AU - Sanchez-Garcia, Elsa

AU - Boyd, Helen

AU - Ottmann, Christian

AU - Doveston, Richard G.

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N2 - The interaction between the adapter protein 14-3-3σ and transcription factor p53 is important for preserving the tumor-suppressor functions of p53 in the cell. A phosphorylated motif within the C-terminal domain (CTD) of p53 is key for binding to the amphipathic groove of 14-3-3. This motif is unique among 14-3-3 binding partners, and the precise dynamics of the interaction is not yet fully understood. Here, we investigate this interaction at the molecular level by analyzing the binding of different length p53 CTD peptides to 14-3-3σ using ITC, SPR, NMR, and MD simulations. We observed that the propensity of the p53 peptide to adopt turn-like conformation plays an important role in the binding to the 14-3-3σ protein. Our study contributes to elucidate the molecular mechanism of the 14-3-3-p53 binding and provides useful insight into how conformation properties of a ligand influence protein binding.

AB - The interaction between the adapter protein 14-3-3σ and transcription factor p53 is important for preserving the tumor-suppressor functions of p53 in the cell. A phosphorylated motif within the C-terminal domain (CTD) of p53 is key for binding to the amphipathic groove of 14-3-3. This motif is unique among 14-3-3 binding partners, and the precise dynamics of the interaction is not yet fully understood. Here, we investigate this interaction at the molecular level by analyzing the binding of different length p53 CTD peptides to 14-3-3σ using ITC, SPR, NMR, and MD simulations. We observed that the propensity of the p53 peptide to adopt turn-like conformation plays an important role in the binding to the 14-3-3σ protein. Our study contributes to elucidate the molecular mechanism of the 14-3-3-p53 binding and provides useful insight into how conformation properties of a ligand influence protein binding.

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