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 结合蛋白是许多大型复合物的重要组成部分，这些复合物执行转录、剪接和 DNA 修复等基本过程。许多 RNA 结合蛋白具有对正常 RNA 加工至关重要的低复杂性结构域。这些低复杂性结构域的结构和功能仍不清楚，特别是在肉瘤融合（FUS）疾病中，它是二十九个结构域之一。 FUS 的低复杂性结构域被认为通过形成动态的结构来促进正常 RNA 代谢中的相互作用。然而，FUS 低复杂性域之间的过度自关联被认为会导致肌萎缩侧索亚型病理性神经元包涵体的形成。硬化症和额颞叶痴呆是不可逆的神经退行性疾病，缺乏有效的治疗方法。此外，FUS 低复杂性结构域通过染色体易位与某些 DNA 结合结构域融合，导致基因表达不受控制，从而导致一系列侵袭性儿童结构癌症。 FUS 组装体的结构以及预防疾病相关聚集体和复合物的正常机制目前尚不清楚，因为它们对于结构生物学的传统技术来说是不可见的。然而，最近的技术进步现在使得动态可视化成为可能。该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来绘制 FUS 低复杂性结构域沿其组装的结构和分子接触图。途径，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，3) 确定自组装 FUS 和 FUS 之间形成的复合物的原子细节RNA 聚合酶 II 的 C 末端结构域 (CTD)；并评估通过修饰 FUS 低复杂性结构域来改变 FUS 和 CTD 之间的相互作用如何影响转录激活和癌变潜力。这些 FUS 组装研究将提供必要的结构。 /关于抑制肌萎缩侧索硬化症类型病理蛋白关联的未来药理学靶点的功能信息，此外，由于 FUS 只是许多含有易于聚集的低复杂性结构域的必需 RNA 结合蛋白之一，因此该项目的结果将作为了解整个相互作用的基础。蛋白质类别并纠正其在疾病中的功能障碍。

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）

Computational modeling highlights the role of the disordered Formin Homology 1 domain in profilin-actin transfer.

计算模型强调了无序的 Formin Homology 1 结构域在 profilin-actin 转移中的作用。

DOI：
发表时间：
2018
期刊：
影响因子：
3.5
作者：
Horan, Brandon G;Zerze, Gül H;Kim, Young C;Vavylonis, Dimitrios;Mittal, Jeetain
通讯作者：
Mittal, Jeetain

Physiological, Pathological, and Targetable Membraneless Organelles in Neurons.

神经元中的生理、病理和可靶向无膜细胞器。

DOI：
发表时间：
2019-10
期刊：
影响因子：
15.9
作者：
Ryan, Veronica H;Fawzi, Nicolas L
通讯作者：
Fawzi, Nicolas L

Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis.

具有内源性 TDP-43 突变的小鼠表现出剪接功能的增强和肌萎缩侧索硬化症的特征。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Fratta, Pietro;Sivakumar, Prasanth;Humphrey, Jack;Lo, Kitty;Ricketts, Thomas;Oliveira, Hugo;Brito;Kalmar, Bernadett;Ule, Agnieszka;Yu, Yichao;Birsa, Nicol;Bodo, Cristian;Collins, Toby;Conicella, Alexander E;Mejia Maza, Alan;Ma
通讯作者：
Ma

Molecular interactions underlying liquid-liquid phase separation of the FUS low-complexity domain.

FUS 低复杂性域液-液相分离的分子相互作用。

DOI：
发表时间：
2019
期刊：
影响因子：
16.8
作者：
Murthy, Anastasia C;Dignon, Gregory L;Kan, Yelena;Zerze, Gül H;Parekh, Sapun H;Mittal, Jeetain;Fawzi, Nicolas L
通讯作者：
Fawzi, Nicolas L

Biomolecular Phase Separation: From Molecular Driving Forces to Macroscopic Properties.

生物分子相分离：从分子驱动力到宏观特性。