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p53 转录激活结构域介导与多聚-PR/GR 的结合和相分离。

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

机构信息

Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Department of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria.

BioTechMed-Graz, 8010 Graz, Austria.

出版信息

Int J Mol Sci. 2021 Oct 22;22(21):11431. doi: 10.3390/ijms222111431.

DOI:10.3390/ijms222111431
PMID:34768862
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8583712/
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.

摘要

最常见的肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 的遗传原因是多聚 PR/GR 二肽重复的存在，这些重复由染色体 9 开放阅读框 72 (C9orf72) 基因编码。最近表明，多聚 PR/GR 改变染色质可及性，从而导致肿瘤抑制因子 p53 在几种神经退行性疾病模型中的稳定性和转录活性增强。p53 蛋白水平的降低可防止多聚 PR 和部分防止多聚 GR 神经毒性。此外，在模式生物中，p53 蛋白水平的降低可防止多聚 PR 的神经毒性。在这里，我们旨在研究 p53 如何有助于多聚 PR/GR 介导的神经退行性变的详细分子机制。我们使用核磁共振 (NMR) 光谱、荧光偏振、浊度测定和微分干涉对比 (DIC) 显微镜等生物物理技术的组合，发现 p53 与多聚 PR/GR 物理相互作用，并触发 p53 的液-液相分离。我们确定了 p53 转录激活结构域 2 (TAD2) 是 PR25/GR25 的主要结合位点，并表明多聚 PR/GR 与 p53 的结合是通过静电和/或疏水相互作用网络介导的。我们的发现可能有助于理解 p53 在多聚 PR/GR 相关神经退行性变中的机制作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e004/8583712/86bffa303168/ijms-22-11431-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e004/8583712/0495293fe9f0/ijms-22-11431-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e004/8583712/86bffa303168/ijms-22-11431-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e004/8583712/0495293fe9f0/ijms-22-11431-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e004/8583712/fe6ef07c3285/ijms-22-11431-g002.jpg
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