p53 Transactivation Domain Mediates Binding and Phase Separation with Poly-PR/GR.
Int J Mol Sci
; 22(21)2021 Oct 22.
Article
em En
| MEDLINE
| ID: mdl-34768862
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteína Supressora de Tumor p53
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Dipeptídeos
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Demência Frontotemporal
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Proteína C9orf72
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Esclerose Lateral Amiotrófica
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article