Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Usluer, S; Spreitzer, E; Bourgeois, B; Madl, T.
p53 Transactivation Domain Mediates Binding and Phase Separation with Poly-PR/GR.
Int J Mol Sci. 2021; 22(21):
Doi: 10.3390/ijms222111431
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- Führende Autor*innen der Med Uni Graz
- Madl Tobias
- Usluer Sinem
- Co-Autor*innen der Med Uni Graz
- Bourgeois Benjamin Michel Rene
- Spreitzer Emil
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Amyotrophic Lateral Sclerosis - genetics, pathology
- Binding Sites - administration & dosage
- C9orf72 Protein - genetics, metabolism
- Dipeptides - metabolism
- Fluorescence Polarization - administration & dosage
- Frontotemporal Dementia - genetics, pathology
- Humans - administration & dosage
- Intrinsically Disordered Proteins - genetics, metabolism
- Nuclear Magnetic Resonance, Biomolecular - administration & dosage
- Protein Interaction Domains and Motifs - physiology
- Transcriptional Activation - genetics
- Tumor Suppressor Protein p53 - genetics, metabolism
- Find related publications in this database (Keywords)
- poly-PR/GR
- neurodegenerative disease
- LLPS
- p53
- intrinsically disordered domains
- membraneless organelles