Extra-translational roles of aminoacyl tRNA synthetases in connection to disease

氨酰 tRNA 合成酶与疾病相关的翻译外作用

• 批准号: 8536318
• 负责人: Xiang-Lei Yang
• 金额: $ 34.47万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-06 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8536318
• 关键词: Amino Acyl-tRNA Synthetases; Aminoacylation; Amyotrophic Lateral Sclerosis; Apoptosis; Binding; C-terminal; Catalysis; Cells; Charcot-Marie-Tooth Disease; Cytoplasmic Tail; Death Domain; Disease; Enzyme Activation; Enzymes; Family; Frequencies; Genes; Glycine; Glycine-Specific tRNA; Glycine-tRNA Ligase; Goals; Hereditary Motor and Sensory Neuropathies; Homeostasis; Human; Individual; Knowledge; Ligation; Light; Mediating; Modification; Mutation; Neurons; Parkinson Disease; Pathway interactions; Peripheral Nervous System Diseases; Phenotype; Physical condensation; Population; Protein Biosynthesis; Proteins; Reaction; Role; Signal Transduction; Testing; Transfer RNA; Tumor Necrosis Factor Receptor; Tyrosine-tRNA Ligase; Ubiquitin; Ubiquitin Like Proteins; Work; YARS gene; abstracting; hereditary neuropathy; human disease; member; nervous system disorder; public health relevance

DESCRIPTION (provided by applicant): Extra-translational role of aminoacyl-tRNA synthetases in connection to disease Abstract: My goal is to understand the expanded functions of glycyl-tRNA synthetase (GlyRS) and how they connect with Charcot-Marie-Tooth (CMT) diseases. GlyRS is one of 20 members of the aminoacyl-tRNA synthetase (AARS) family that catalyzes aminoacylation of transfer tRNAin the first step of protein synthesis. Dominant mutations of GARS (gene for GlyRS) and YARS (gene for tyrosyl-tRNA synthetase) have been identified in the human population to cause Charcot-Marie-Tooth (CMT) diseases. Also known as hereditary motor and sensory neuropathies, CMT diseases are the most common heritable peripheral neuropathy, occurring with a frequency of approximately 1 in 2500 individuals. The CMT phenotype does not arise from a reduction in the essential aminoacylation function. This observation led to our hypothesis that these two tRNA synthetases have expanded functions (beyond aminoacylation) that are critical to understanding their connection to CMT. The focus of the proposal is on GlyRS. A search for interaction partners of GlyRS identified Daxx, a protein that interacts with the cytoplasmic domain of Fas. Fas is a member of the tumor necrosis factor receptor superfamily, and the Fas-Daxx interaction enhances Fas-mediated apoptosis. Significantly, The Fas-Daxx pathway is implicated in CMT, as well as in many other neurological disorders including Amyotrophic Lateral Sclerosis and Parkinson's disease. These considerations raised the possibility that the interaction between GlyRS and Daxx is relevant to the CMT disease-causing mechanism. Surprisingly, we found that a modified form of GlyRS specifically interacts with Daxx. We have identified the modifier of GlyRS to be a ubiquitin-like protein called NEDD8. NEDDylation is known to regulate the function of its substrates. Interestingly, the residue on NEDD8 for conjugation to substrate is the C-terminal glycine, which is conserved in ubiquitin and in almost all ubiquitin-like proteins. The first reaction in NEDDylation is the adenylation of the C- terminal glycine by condensation with ATP. It is chemically the same reaction as the first step of catalysis by GlyRS in aminoacylation. This consideration led us to propose that GlyRS is involved in the NEDDylation of Daxx which, in turn, regulates Daxx-mediated apoptosis. Indeed, we found that GlyRS-associated Daxx is NEDDylated. Thus, the work proposed here will advance understanding of the extra-translational roles of AARS and their possible connection to human disease. PUBLIC HEALTH RELEVANCE: Narrative This project will aid in understanding how tRNA synthetases function in connection to Charcot-Marie-Tooth disease, which is the most common hereditary neuropathy. The knowledge we gain in this study will also shed light on other neurological diseases such as Amyotrophic Lateral Sclerosis (Lou Gehrig's disease) and Parkinson's disease.

摘要：我的目标是了解glyyl - trna合成酶（GlyRS）的扩展功能以及它们如何与charco - marie - tooth （CMT）疾病联系在一起。GlyRS是氨基酰基- trna合成酶（AARS）家族的20个成员之一，该家族催化转移trna的氨基酰化，这是蛋白质合成的第一步。GARS （GlyRS基因）和YARS （tyroyl - trna合成酶基因）的显性突变已在人群中被确定为导致沙克-玛丽-牙（CMT）病。CMT疾病也被称为遗传性运动和感觉神经病，是最常见的遗传性周围神经病变，发生频率约为2500人中有1人。CMT表型不是由必需的氨基酰化功能的减少引起的。这一观察结果导致了我们的假设，即这两种tRNA合成酶具有扩展功能（超越氨基酰化），这对于理解它们与CMT的联系至关重要。该提案的重点是GlyRS。对GlyRS相互作用伙伴的研究发现了Daxx，一种与Fas细胞质结构域相互作用的蛋白质。Fas是肿瘤坏死因子受体超家族的成员，Fas- daxx相互作用增强Fas介导的细胞凋亡。值得注意的是，Fas-Daxx通路与CMT以及许多其他神经系统疾病（包括肌萎缩性侧索硬化症和帕金森病）有关。这些考虑提出了GlyRS和Daxx之间的相互作用与CMT致病机制相关的可能性。令人惊讶的是，我们发现GlyRS的一种修饰形式特异性地与Daxx相互作用。我们已经确定GlyRS的修饰剂是一种泛素样蛋白，称为NEDD8。已知neddyation调节其底物的功能。有趣的是，NEDD8上与底物结合的残基是c端甘氨酸，它在泛素和几乎所有泛素样蛋白中都是保守的。neddyation的第一个反应是C端甘氨酸与ATP缩合的腺苷化。它在化学上与GlyRS催化氨基酰化的第一步反应相同。考虑到这一点，我们提出GlyRS参与Daxx的neddyation，进而调节Daxx介导的细胞凋亡。事实上，我们发现glyrs相关的Daxx是neddyated的。因此，这里提出的工作将促进对AARS的翻译外作用及其与人类疾病的可能联系的理解。