Allosteric changes in HDM2 by the ATM phospho-mimetic S395D mutation: Implications on HDM2 function

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00209805%3A_____%2F19%3A00078258" target="_blank" >RIV/00209805:_____/19:00078258 - isvavai.cz</a>

Výsledek na webu

<a href="https://portlandpress.com/biochemj/article-lookup/doi/10.1042/BCJ20190687" target="_blank" >https://portlandpress.com/biochemj/article-lookup/doi/10.1042/BCJ20190687</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1042/BCJ20190687" target="_blank" >10.1042/BCJ20190687</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Allosteric changes in HDM2 by the ATM phospho-mimetic S395D mutation: Implications on HDM2 function

Popis výsledku v původním jazyce

Allosteric changes imposed by post-translational modifications regulate and differentiate the functions of proteins with intrinsic disorder regions. HDM2 is a hub protein with a large interactome and with different cellular functions. It is best known for its regulation of the p53 tumour suppressor. Under normal cellular conditions, HDM2 ubiquitinates and degrades p53 by the 26S proteasome but after DNA damage, HDM2 switches from a negative to a positive regulator of p53 by binding to p53 mRNA to promote translation of the p53 mRNA. This change in activity is governed by the ATM kinase via phosphorylation on serine 395 and is mimicked by the S395D phosphomimetic mutant. Here we have used different approaches to show that this event is accompanied by a specific change in the HDM2 structure that affects the HDM2 interactome, such as the N-termini HDM2 - p53 protein-protein interaction. These data will give a better understanding of how HDM2 switches from a negative to a positive regulator of p53 and gain new insights into the control of the HDM2 structure and its interactome under different cellular conditions and help identify interphases as potential targets for new drug developments.

Název v anglickém jazyce

Allosteric changes in HDM2 by the ATM phospho-mimetic S395D mutation: Implications on HDM2 function

Popis výsledku anglicky

Allosteric changes imposed by post-translational modifications regulate and differentiate the functions of proteins with intrinsic disorder regions. HDM2 is a hub protein with a large interactome and with different cellular functions. It is best known for its regulation of the p53 tumour suppressor. Under normal cellular conditions, HDM2 ubiquitinates and degrades p53 by the 26S proteasome but after DNA damage, HDM2 switches from a negative to a positive regulator of p53 by binding to p53 mRNA to promote translation of the p53 mRNA. This change in activity is governed by the ATM kinase via phosphorylation on serine 395 and is mimicked by the S395D phosphomimetic mutant. Here we have used different approaches to show that this event is accompanied by a specific change in the HDM2 structure that affects the HDM2 interactome, such as the N-termini HDM2 - p53 protein-protein interaction. These data will give a better understanding of how HDM2 switches from a negative to a positive regulator of p53 and gain new insights into the control of the HDM2 structure and its interactome under different cellular conditions and help identify interphases as potential targets for new drug developments.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

The Biochemical journal

ISSN

0264-6021

e-ISSN

—

Svazek periodika

476

Číslo periodika v rámci svazku

21

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

11

Strana od-do

3401-3411

Kód UT WoS článku

000509877500018

EID výsledku v databázi Scopus

2-s2.0-85075089900