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).

描述：这项研究的长期目标是了解如何将泛素结构域视为靶向信号。泛素结构域是一种多样化且广泛使用的靶向信号，后翻译后附着在各种细胞蛋白上。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）以及应力反应（蛋白质质量控制，神经变性和基因组完整性）有关。域的结合可修改目标蛋白的定位或活性。单个泛素与组蛋白的结合参与染色质和DMA事务，以及作为内体分类途径中的分类信号。 NEDD8共轭调节了泛素E3 Liganses，而SUMO-1（小型泛素样修饰剂）共轭共轭广泛参与核蛋白质代谢性。靶蛋白的聚泛素化（或sumoylation）是通过通过赖氨酸残基附着在另一种泛素到另一种泛素来实现的。 K48偶联的聚泛素是用于将靶蛋白传递到蛋白酶体的蛋白质水解的信号，而K63连接的链参与NFKB途径中的信号复合物，并在DNA修复中起一些不确定的作用。尽管这些链的功能以及Polysumo-2/3链的功能是完全未知的，但还观察到了通过赖氨酸6,11、29和33的连接。统一的假设是，有特定的受体或适配器专门识别不同的泛素结构域和环境，随后将共轭蛋白引导到适当的细胞命运。这项研究建议通过研究多泛素识别并定义区分不同版本的泛素结构域之间的受体和结合蛋白来定义不同链链接的某些潜在作用。这里使用了两种方法。首先，一种定向方法使用去泛素化酶作为对多泛素识别的模型，无论是通过直接识别（USP5/等肽酶T，AIM 1）或通过适配器辅助识别特定底物的识别（BAP1，AIM 2）。其次，现代系统生物学方法利用了我们对多泛素链类似物的合成来鉴定具有特异性的泛素结合蛋白，这些蛋白质对于不同的泛素结构域和不同的体系结构（AIM 3）。