Understanding the interaction of 14-3-3 proteins with hDMX and hDM2: a structural and biophysical study

Sonja Srdanović; Madita Wolter; Chi H. Trinh; Christian Ottmann; Stuart L. Warriner; Andrew J. Wilson

doi:10.1111/febs.16433

Understanding the interaction of 14-3-3 proteins with hDMX and hDM2: a structural and biophysical study

Sonja Srdanović
, Madita Wolter
, Chi H. Trinh
, Christian Ottmann
, Stuart L. Warriner
, Andrew J. Wilson (Corresponding author)

Research output: Contribution to journal › Article › Academic › peer-review

10 Citations (Scopus)

182 Downloads (Pure)

Abstract

p53 plays a critical role in regulating diverse biological processes: DNA repair, cell cycle arrest, apoptosis and senescence. The p53 pathway has therefore served as the focus of multiple drug-discovery efforts. p53 is negatively regulated by hDMX and hDM2; prior studies have identified 14-3-3 proteins as hDMX and hDM2 client proteins. 14-3-3 proteins are adaptor proteins that modulate localization, degradation and interactions of their targets in response to phosphorylation. Thus, 14-3-3 proteins may indirectly modulate the interaction between hDMX or hDM2 and p53 and represent potential targets for modulation of the p53 pathway. In this manuscript, we report on the biophysical and structural characterization of peptide/protein interactions that are representative of the interaction between 14-3-3 and hDMX or hDM2. The data establish that proximal phosphosites spaced ~20–25 residues apart in both hDMX and hDM2 co-operate to facilitate high-affinity 14-3-3 binding and provide structural insight that can be utilized in future stabilizer/inhibitor discovery efforts.

Original language	English
Pages (from-to)	5341-5358
Number of pages	18
Journal	FEBS Journal
Volume	289
Issue number	17
DOIs	https://doi.org/10.1111/febs.16433
Publication status	Published - Sept 2022

Funding

We would like to thank Dr Iain Manfield for his support with ITC and SPR measurements and Gavin O’Mahony, AstraZeneca for ongoing collaboration and useful discussions. This work was supported by EPSRC (EP/N013573/1 and EP/KO39292/1). This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie programme H2020-MSCA-ITN-2015 grant number 675179 (The TASPPI project). This work was supported by Diamond beam time awarded under proposal number MX19248. AJW wishes to acknowledge the support of a Royal Society Leverhulme Trust Senior Fellowship (SRF\R1\191087)

Funders	Funder number
Marie Skłodowska‐Curie
Engineering and Physical Sciences Research Council	EP/KO39292/1, EP/N013573/1
European Union's Horizon 2020 - Research and Innovation Framework Programme	MX19248, 675179

Keywords

14-3-3 proteins
hDM2 and hDMX
p53 pathway
structural biology

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10.1111/febs.16433

pdfFinal published version, 1.22 MBLicence: CC BY

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title = "Understanding the interaction of 14-3-3 proteins with hDMX and hDM2: a structural and biophysical study",

abstract = "p53 plays a critical role in regulating diverse biological processes: DNA repair, cell cycle arrest, apoptosis and senescence. The p53 pathway has therefore served as the focus of multiple drug-discovery efforts. p53 is negatively regulated by hDMX and hDM2; prior studies have identified 14-3-3 proteins as hDMX and hDM2 client proteins. 14-3-3 proteins are adaptor proteins that modulate localization, degradation and interactions of their targets in response to phosphorylation. Thus, 14-3-3 proteins may indirectly modulate the interaction between hDMX or hDM2 and p53 and represent potential targets for modulation of the p53 pathway. In this manuscript, we report on the biophysical and structural characterization of peptide/protein interactions that are representative of the interaction between 14-3-3 and hDMX or hDM2. The data establish that proximal phosphosites spaced \textasciitilde{}20{\textendash}25 residues apart in both hDMX and hDM2 co-operate to facilitate high-affinity 14-3-3 binding and provide structural insight that can be utilized in future stabilizer/inhibitor discovery efforts.",

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author = "Sonja Srdanovi{\'c} and Madita Wolter and Trinh, \{Chi H.\} and Christian Ottmann and Warriner, \{Stuart L.\} and Wilson, \{Andrew J.\}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors. The FEBS Journal published by John Wiley \& Sons Ltd on behalf of Federation of European Biochemical Societies.",

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AU - Wolter, Madita

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AU - Ottmann, Christian

AU - Warriner, Stuart L.

AU - Wilson, Andrew J.

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N2 - p53 plays a critical role in regulating diverse biological processes: DNA repair, cell cycle arrest, apoptosis and senescence. The p53 pathway has therefore served as the focus of multiple drug-discovery efforts. p53 is negatively regulated by hDMX and hDM2; prior studies have identified 14-3-3 proteins as hDMX and hDM2 client proteins. 14-3-3 proteins are adaptor proteins that modulate localization, degradation and interactions of their targets in response to phosphorylation. Thus, 14-3-3 proteins may indirectly modulate the interaction between hDMX or hDM2 and p53 and represent potential targets for modulation of the p53 pathway. In this manuscript, we report on the biophysical and structural characterization of peptide/protein interactions that are representative of the interaction between 14-3-3 and hDMX or hDM2. The data establish that proximal phosphosites spaced ~20–25 residues apart in both hDMX and hDM2 co-operate to facilitate high-affinity 14-3-3 binding and provide structural insight that can be utilized in future stabilizer/inhibitor discovery efforts.

AB - p53 plays a critical role in regulating diverse biological processes: DNA repair, cell cycle arrest, apoptosis and senescence. The p53 pathway has therefore served as the focus of multiple drug-discovery efforts. p53 is negatively regulated by hDMX and hDM2; prior studies have identified 14-3-3 proteins as hDMX and hDM2 client proteins. 14-3-3 proteins are adaptor proteins that modulate localization, degradation and interactions of their targets in response to phosphorylation. Thus, 14-3-3 proteins may indirectly modulate the interaction between hDMX or hDM2 and p53 and represent potential targets for modulation of the p53 pathway. In this manuscript, we report on the biophysical and structural characterization of peptide/protein interactions that are representative of the interaction between 14-3-3 and hDMX or hDM2. The data establish that proximal phosphosites spaced ~20–25 residues apart in both hDMX and hDM2 co-operate to facilitate high-affinity 14-3-3 binding and provide structural insight that can be utilized in future stabilizer/inhibitor discovery efforts.

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Understanding the interaction of 14-3-3 proteins with hDMX and hDM2: a structural and biophysical study

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