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Ubiquitin-Dependent Proteolysis: Specificity & Mechanism

泛素依赖性蛋白水解：特异性

基本信息

批准号：
7911607
负责人：
KEITH D WILKINSON
金额：
$ 34.08万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1982
资助国家：
美国
起止时间：
1982-02-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7911607
关键词：
Address Affinity Apoptosis Architecture Area BRCA1 Associated Protein-1 Binding Binding Proteins Cancer Control Characteristics Chromatin Collaborations Complex DNA Repair Deubiquitinating Enzyme Enzymes Event Follow-Up Studies Genome Goals Growth Histones Infection Inflammation IsoT enzyme Length Link Lysine Measures Modeling Molecular Monoubiquitination Nature Nerve Degeneration Nuclear Nuclear Protein Nuclear Proteins Pathway interactions Physiological Play Polyubiquitin Post-Translational Protein Processing Protein Isoforms Proteins Proteolysis Proteome Proteomics Quality Control Regulation Research Research Personnel Role Signal Pathway Signal Transduction Site Sorting - Cell Movement Specificity System Systems Biology Technology Transcriptional Regulation Ubiquitin Ubiquitination Work analog biological adaptation to stress histone modification interest multicatalytic endopeptidase complex programs protein degradation receptor receptor binding receptor function response scaffold targeted delivery

项目摘要

DESCRIPTION: The long-term goal of this research is to understand how the ubiquitin domain is recognized as a targeting signal. The ubiquitin domain is a diverse and widely used targeting signal that is post- translationally attached to a variety of cellular proteins. The ubiquitin pathway is implicated in growth control (cancer and apoptosis), signal transduction (inflammation and transcriptional control), and the stress response (protein quality control, neurodegeneration, and genome integrity). Conjugation of the domain serves to modify the localization or activities of the target protein. Conjugation of a single ubiquitin to histones is involved in chromatin and DMA transactions and as a sorting signal in endosomal sorting pathways. NEDD8 conjugation regulated ubiquitin E3 liganses while SUMO-1 (small ubiquitin-like modifier) conjugation is widely involved in nuclear protein metaboslism. Poly ubiquitination (or SUMOylation) of target proteins is achieved by attachment of one ubiquitin to another through lysine residues. K48-Iinked polyubiquitin is a signal for delivery of the target protein to the proteasome for proteolysis while K63-linked chains are involved in assembling signaling complexes in the NFkB pathway and play some undetermined role in DNA repair. Linkages through lysines 6,11, 29, and 33 are also observed, although the function of these chains, as well as that of polySUMO-2/3 chains is completely unknown. The unifying hypothesis is that there are specific receptors or adapters that specifically recognize the different ubiquitin domains and contexts and that subsequently direct the conjugated protein to the appropriate cellular fate. This study proposes to define some of the potential roles of the different chain linkages by studying polyubiquitin recognition and defining the receptors and binding proteins that distinguish among different version of the ubiquitin domain. Two approaches are used here. First, a directed approach uses deubiquitinating enzymes as a model for specific recognition of polyubiquitin, either by direct recognition (USP5/isopeptidase T, Aim 1) or by adapter-assisted recognition of specific substrates (BAP1, Aim 2). Second, a modern systems biology approach takes advantage of our synthesis of polyubiquitin chain analogs to identify ubiquitin-binding proteins with specificity for different ubiquitin domains and different architectures (Aim 3).

本研究的长期目标是了解泛素结构域如何被识别为靶向信号。泛素结构域是一种多样且广泛使用的靶向信号，其在免疫后连接到多种细胞蛋白。泛素途径与生长控制（癌症和凋亡）、信号转导（炎症和转录控制）和应激反应（蛋白质质量控制、神经变性和基因组完整性）有关。结构域的缀合用于修饰靶蛋白的定位或活性。单个泛素与组蛋白的缀合涉及染色质和DMA交易，并且作为内体分选途径中的分选信号。NEDD 8缀合调节泛素E3配体，而SUMO-1（小泛素样修饰物）缀合广泛参与核蛋白代谢。靶蛋白的多聚泛素化（或SUMO化）是通过赖氨酸残基将一个泛素连接到另一个泛素上来实现的。K48-连接的多聚泛素是将靶蛋白递送至蛋白酶体以进行蛋白水解的信号，而K63-连接的链参与NF κ B途径中的信号复合物的组装，并且在DNA修复中发挥一些未确定的作用。还观察到通过赖氨酸6、11、29和33的连接，尽管这些链以及polySUMO-2/3链的功能完全未知。统一的假设是，存在特异性受体或衔接子，其特异性识别不同的泛素结构域和背景，并随后将缀合的蛋白质引导至适当的细胞命运。本研究提出通过研究多聚泛素识别和定义区分不同版本的泛素结构域的受体和结合蛋白来定义不同链连接的一些潜在作用。这里使用了两种方法。首先，定向方法使用去泛素化酶作为多聚泛素特异性识别的模型，通过直接识别（USP 5/异肽酶T，Aim 1）或通过特定底物的衔接子辅助识别（BAP 1，Aim 2）。第二，现代系统生物学方法利用我们的多聚泛素链类似物的合成来鉴定对不同泛素结构域和不同结构具有特异性的泛素结合蛋白（目的3）。