p53 Transactivation Domain Mediates Binding and Phase Separation with Poly-PR/GR

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the presence of poly-PR/GR dipeptide repeats, which are encoded by the chromosome 9 open reading frame 72 (C9orf72) gene. Recently, it was shown that poly-PR/GR alters chromatin accessibility, w...

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Autores principales:	Sinem Usluer, Emil Spreitzer, Benjamin Bourgeois, Tobias Madl
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	poly-PR/GR neurodegenerative disease LLPS p53 intrinsically disordered domains membraneless organelles Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/965c28834c58400c9c7371f54ff27797
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id	oai:doaj.org-article:965c28834c58400c9c7371f54ff27797
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spelling	oai:doaj.org-article:965c28834c58400c9c7371f54ff277972021-11-11T16:53:58Zp53 Transactivation Domain Mediates Binding and Phase Separation with Poly-PR/GR10.3390/ijms2221114311422-00671661-6596https://doaj.org/article/965c28834c58400c9c7371f54ff277972021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11431https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the presence of poly-PR/GR dipeptide repeats, which are encoded by the chromosome 9 open reading frame 72 (C9orf72) gene. Recently, it was shown that poly-PR/GR alters chromatin accessibility, which results in the stabilization and enhancement of transcriptional activity of the tumor suppressor p53 in several neurodegenerative disease models. A reduction in p53 protein levels protects against poly-PR and partially against poly-GR neurotoxicity in cells. Moreover, in model organisms, a reduction of p53 protein levels protects against neurotoxicity of poly-PR. Here, we aimed to study the detailed molecular mechanisms of how p53 contributes to poly-PR/GR-mediated neurodegeneration. Using a combination of biophysical techniques such as nuclear magnetic resonance (NMR) spectroscopy, fluorescence polarization, turbidity assays, and differential interference contrast (DIC) microscopy, we found that p53 physically interacts with poly-PR/GR and triggers liquid–liquid phase separation of p53. We identified the p53 transactivation domain 2 (TAD2) as the main binding site for PR25/GR25 and showed that binding of poly-PR/GR to p53 is mediated by a network of electrostatic and/or hydrophobic interactions. Our findings might help to understand the mechanistic role of p53 in poly-PR/GR-associated neurodegeneration.Sinem UsluerEmil SpreitzerBenjamin BourgeoisTobias MadlMDPI AGarticlepoly-PR/GRneurodegenerative diseaseLLPSp53intrinsically disordered domainsmembraneless organellesBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11431, p 11431 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	poly-PR/GR neurodegenerative disease LLPS p53 intrinsically disordered domains membraneless organelles Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	poly-PR/GR neurodegenerative disease LLPS p53 intrinsically disordered domains membraneless organelles Biology (General) QH301-705.5 Chemistry QD1-999 Sinem Usluer Emil Spreitzer Benjamin Bourgeois Tobias Madl p53 Transactivation Domain Mediates Binding and Phase Separation with Poly-PR/GR
description	The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the presence of poly-PR/GR dipeptide repeats, which are encoded by the chromosome 9 open reading frame 72 (C9orf72) gene. Recently, it was shown that poly-PR/GR alters chromatin accessibility, which results in the stabilization and enhancement of transcriptional activity of the tumor suppressor p53 in several neurodegenerative disease models. A reduction in p53 protein levels protects against poly-PR and partially against poly-GR neurotoxicity in cells. Moreover, in model organisms, a reduction of p53 protein levels protects against neurotoxicity of poly-PR. Here, we aimed to study the detailed molecular mechanisms of how p53 contributes to poly-PR/GR-mediated neurodegeneration. Using a combination of biophysical techniques such as nuclear magnetic resonance (NMR) spectroscopy, fluorescence polarization, turbidity assays, and differential interference contrast (DIC) microscopy, we found that p53 physically interacts with poly-PR/GR and triggers liquid–liquid phase separation of p53. We identified the p53 transactivation domain 2 (TAD2) as the main binding site for PR25/GR25 and showed that binding of poly-PR/GR to p53 is mediated by a network of electrostatic and/or hydrophobic interactions. Our findings might help to understand the mechanistic role of p53 in poly-PR/GR-associated neurodegeneration.
format	article
author	Sinem Usluer Emil Spreitzer Benjamin Bourgeois Tobias Madl
author_facet	Sinem Usluer Emil Spreitzer Benjamin Bourgeois Tobias Madl
author_sort	Sinem Usluer
title	p53 Transactivation Domain Mediates Binding and Phase Separation with Poly-PR/GR
title_short	p53 Transactivation Domain Mediates Binding and Phase Separation with Poly-PR/GR
title_full	p53 Transactivation Domain Mediates Binding and Phase Separation with Poly-PR/GR
title_fullStr	p53 Transactivation Domain Mediates Binding and Phase Separation with Poly-PR/GR
title_full_unstemmed	p53 Transactivation Domain Mediates Binding and Phase Separation with Poly-PR/GR
title_sort	p53 transactivation domain mediates binding and phase separation with poly-pr/gr
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/965c28834c58400c9c7371f54ff27797
work_keys_str_mv	AT sinemusluer p53transactivationdomainmediatesbindingandphaseseparationwithpolyprgr AT emilspreitzer p53transactivationdomainmediatesbindingandphaseseparationwithpolyprgr AT benjaminbourgeois p53transactivationdomainmediatesbindingandphaseseparationwithpolyprgr AT tobiasmadl p53transactivationdomainmediatesbindingandphaseseparationwithpolyprgr
_version_	1718432190208933888

p53 Transactivation Domain Mediates Binding and Phase Separation with Poly-PR/GR

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