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Turning off the molecular switch for pathological self-assembly of FUS

关闭FUS病理自组装的分子开关

基本信息

批准号：
9900835
负责人：
Nicolas Lux Fawzi
金额：
$ 33万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-07 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900835
关键词：
Affect Amyotrophic Lateral Sclerosis Area Aromatic Amino Acids Binding Biochemical Biophysics C-terminal Cancerous Cell model Charge Chromosomal translocation Code Complex Computer Simulation Consensus Cytoplasm DNA Binding Domain DNA Polymerase II DNA Repair Data Disease Family Family member Foundations Frequencies Functional disorder Future Gene Expression Genetic Transcription Glutamine Glycine Goals Human In Vitro Knowledge Lead Link Liquid substance Malignant Childhood Neoplasm Malignant Neoplasms Maps Mediating Modeling Modification Molecular Mutation N-terminal NMR Spectroscopy Nature Neurodegenerative Disorders Neurons Nuclear Oncogenic Pathologic Pathway interactions Pharmacology Phase Phosphorylation Phosphorylation Site Post-Translational Protein Processing Process Proteins Publishing RNA RNA Polymerase II RNA Processing RNA Splicing RNA metabolism RNA-Binding Proteins Resolution Serine Site Specific qualifier value Structure Techniques Testing Toxic effect Transcription Coactivator Transcriptional Activation Tyrosine Visualization Yeast Model System Yeasts base beta pleated sheet design effective therapy experimental study frontotemporal lobar dementia-amyotrophic lateral sclerosis gene repression in vitro Model innovation leukemia monomer multidisciplinary novel novel therapeutics prevent protein aggregation protein structure public health relevance recruit sarcoma self assembly simulation structural biology

项目摘要

DESCRIPTION (provided by applicant): RNA-binding proteins are essential components of numerous large complexes that carry out fundamental processes including transcription, splicing, and DNA repair. Many RNA-binding proteins possess low- complexity domains that are critical to normal RNA-processing functions, but also drive aberrant protein assembly in various types of neurodegenerative disease and cancer. The structure and function of these low complexity domains remain poorly characterized, especially in the context of disease. Fused in Sarcoma (FUS) is one of twenty-nine distinct human RNA-binding proteins that contain an essential putatively unstructured low-complexity domain with unusually low charged residue composition and a high frequency of aromatic amino acids. The low-complexity domain of FUS is thought to facilitate interactions in normal RNA metabolism by forming dynamic associations, enabling tunable, reversible spatial clustering. Yet, excessive self- association between FUS low-complexity domains is believed to result in the formation of pathological neuronal inclusions in sub-types of amyotrophic lateral sclerosis and frontotemporal dementia, which are irreversible neurodegenerative diseases that lack effective treatments. Moreover, fusion of the FUS low- complexity domain to certain DNA-binding domains through chromosomal translocations results in uncontrolled gene expression leading to a family of aggressive cancers of childhood. The structures of FUS assemblies and the normal mechanisms that prevent disease-associated aggregates and complexes are currently unknown because they are invisible to traditional techniques in structural biology. However, recent technical advances now enable visualization of dynamic assemblies of FUS with residue-level resolution. This project will apply advanced nuclear magnetic resonance spectroscopy, molecular simulation, and cell models of FUS-associated diseases to 1) map the structure and molecular contacts of the low-complexity domain of FUS along its assembly pathway, 2) elucidate the molecular details and consequences of disease-associated mutations and posttranslational modifications of the FUS low-complexity domain, and 3) determine atomic details of the complex formed between self-assembled FUS and the C-terminal domain (CTD) of RNA polymerase II; and evaluate how altering the interaction between FUS and CTD, by modifying the FUS low-complexity domain, affects transcriptional activation and cancerous transformation potential. These studies of FUS assembly will provide necessary structure/function information on future pharmacological targets for inhibiting pathological protein associations in types of amyotrophic lateral sclerosis, frontotemporal dementia, leukemia, and sarcoma. Furthermore, because FUS is only one of many essential RNA-binding proteins containing aggregation-prone low complexity domains, the results of the project will serve as the foundation for understanding the interactions of an entire class of proteins and for correcting their dysfunctions in disease.

描述（由申请人提供）：RNA结合蛋白是许多大复合物的基本组分，这些大复合物进行基本过程，包括转录、剪接和DNA修复。许多RNA结合蛋白具有低复杂性结构域，其对正常RNA加工功能至关重要，但也驱动各种类型的神经退行性疾病和癌症中的异常蛋白质组装。这些低复杂性结构域的结构和功能仍然很难表征，特别是在疾病的背景下。融合肉瘤（FUS）是29种不同的人类RNA结合蛋白之一，其包含具有异常低的电荷残基组成和高频率的芳香族氨基酸的必需的非结构化低复杂性结构域。FUS的低复杂性结构域被认为通过形成动态关联，实现可调的、可逆的空间聚类来促进正常RNA代谢中的相互作用。然而，FUS低复杂性结构域之间的过度自缔合被认为导致肌萎缩侧索硬化和额颞叶痴呆的亚型中病理性神经元内含物的形成，这是缺乏有效治疗的不可逆的神经退行性疾病。此外，FUS低复杂性结构域通过染色体易位与某些DNA结合结构域的融合导致不受控制的基因表达，导致儿童侵袭性癌症家族。FUS组装体的结构和防止疾病相关聚集体和复合物的正常机制目前尚不清楚，因为它们对结构生物学中的传统技术是不可见的。然而，最近的技术进步，现在使可视化的动态组件的FUS与残留水平的分辨率。本项目将应用先进的核磁共振波谱、分子模拟和FUS相关疾病的细胞模型，1）绘制FUS低复杂性结构域沿着其组装途径的结构和分子接触，2）阐明FUS低复杂性结构域的疾病相关突变和翻译后修饰的分子细节和后果，和3）确定自组装FUS和RNA聚合酶II的C-末端结构域（CTD）之间形成的复合物的原子细节;并评估通过修饰FUS低复杂性结构域改变FUS和CTD之间的相互作用如何影响转录激活和癌转化潜力。FUS组装的这些研究将为未来抑制肌萎缩性侧索硬化症类型中病理性蛋白质缔合的药理学靶点提供必要的结构/功能信息，额颞叶痴呆白血病和肉瘤此外，由于FUS只是含有聚集倾向低复杂性结构域的许多必需RNA结合蛋白中的一种，因此该项目的结果将作为理解整个RNA结合蛋白相互作用的基础。这类蛋白质并用于纠正疾病中的功能障碍。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The prionlike domain of FUS is multiphosphorylated following DNA damage without altering nuclear localization.

DOI：
10.1091/mbc.e17-12-0735
发表时间：
2018-08-01
期刊：
Molecular biology of the cell
影响因子：
3.3
作者：
Rhoads SN;Monahan ZT;Yee DS;Leung AY;Newcombe CG;O'Meally RN;Cole RN;Shewmaker FP
通讯作者：
Shewmaker FP

Inferring properties of disordered chains from FRET transfer efficiencies.