Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

p53 Transactivation Domain Mediates Binding and Phase Separation With poly-PR/GR

Version 1 : Received: 14 September 2021 / Approved: 15 September 2021 / Online: 15 September 2021 (14:43:48 CEST)

How to cite: Usluer, S.; Spreitzer, E.; Bourgeois, B.; Madl, T. p53 Transactivation Domain Mediates Binding and Phase Separation With poly-PR/GR. Preprints 2021, 2021090265 (doi: 10.20944/preprints202109.0265.v1). Usluer, S.; Spreitzer, E.; Bourgeois, B.; Madl, T. p53 Transactivation Domain Mediates Binding and Phase Separation With poly-PR/GR. Preprints 2021, 2021090265 (doi: 10.20944/preprints202109.0265.v1).

Abstract

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 C9orf72 gene. Recently, it was shown that poly-PR/GR alters chromatin accessibility which results in stabilization and enhancement of transcriptional activity of the tumor suppressor p53 in several neurodegenerative disease models. Reduction of p53 protein levels in cell and model organisms protects against neurotoxicity of poly-PR, and partially protects against neurotoxicity of poly-GR. Here, we aimed to study the detailed molecular mechanisms 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 p53 transactivation domain 2 (TAD2) as the main binding site for PR25/GR25 and show 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.

Keywords

poly-PR/GR; neurodegenerative disease; LLPS; p53; intrinsically disordered domains; membraneless organelles

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