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Adoption of a Turn Conformation Drives the Binding Affinity of p53 C-Terminal Domain Peptides to 14-3-3σ

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posted on 2020-08-03, 08:25 authored by Ave Kuusk, João Filipe Neves, Kenny Bravo-Rodriguez, Anders Gunnarsson, Yasser B Ruiz-Blanco, Michael Ehrmann, Hongming Chen, Isabelle Landrieu, Elsa Sanchez-Garcia, Helen Boyd, Christian Ottmann, Richard G Doveston
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.

Funding

The research is supported by funding from the European Union through the AEGIS project (H2020-MSCA-ITN-2015, Grant Number 67555), TASPPI project (H2020-MSCA-ITN2015, Grant Number 675179), and MSCA IEF (H2020- MSCA-IEF-2016, Grant Number 705188, R.G.D). J.F.N. and I.L. acknowledge LabEx (Laboratory of Excellence) for financial support on the scope of the DISTALZ consortium (ANR, ANR-11-LABX-009). E.S.-G. acknowledges a Plus-3 Grant of the Boehringer-Ingelheim Foundation and the computational time provided by the Computing and Data Facility of the Max Planck Society. The German Research Foundation (DFG) supported this work via the Collaborative Research Center SFB1093 (C.O., M.E., and E.S.-G.) and under Germany’s Excellence Strategy RESOLV EXC2033, Project Number 390677874 (E.S.-G., infrastructure support). We acknowledge F. X. Cantrelle for assistance on NMR data acquisition. The NMR facilities were funded by the Nord Region Council, CNRS, Institut Pasteur de Lille, the European Community (ERDF), and the French Ministry of Research and the University of Lille and by the CTRL CPER cofunded by the European Union with the European Regional Development Fund (ERDF), by the Hauts de France Regional Council (contract no. 17003781), Metropole Europe ́ enne de ́ Lille (contract no. 2016_ESR_05), and French State (contract no. 2017-R3-CTRL-Phase 1). We acknowledge support for the NMR facilities from TGE RMN THC (CNRS, FR-3050) and FRABio (Univ. Lille, CNRS, FR-3688).

History

Citation

ACS Chem. Biol. 2020, 15, 1, 262–271 Publication Date:November 19, 2019 https://doi.org/10.1021/acschembio.9b00893

Version

  • VoR (Version of Record)

Published in

ACS Chemical Biology

Volume

15

Issue

1

Pagination

262 - 271

Publisher

American Chemical Society

issn

1554-8929

eissn

1554-8937

Acceptance date

2019-11-19

Copyright date

2019

Available date

2020-08-03

Notes

OA version https://pubs.acs.org/doi/10.1021/acschembio.9b00893

Spatial coverage

United States

Language

en

Publisher version

https://pubs.acs.org/doi/abs/10.1021/acschembio.9b00893#

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