Identification and characterization of linkage-specific ubiquitin binding element
连接特异性泛素结合元件的鉴定和表征
基本信息
- 批准号:8394560
- 负责人:
- 金额:$ 19.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-21 至 2014-02-28
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): Identification, quantification, and isolation of low abundance proteins from complex mixtures is, at best, a difficult task. This is especially the case
for proteins carrying a post-translational modification (PTM) that affects their half-life or regulatory properties. Examples of such PTMs include phosphorylation, glycosylation (especially O-GlcNAcylation), and ubiquitinylation. In many instances, one PTM can abrogate or enhance other PTMs on the same protein providing exquisite mechanisms for control of the protein's activity. "Fishing" a protein with one particular PTM out of the pool of possible modifie proteins becomes nearly impossible without selective tools. A further complication in the case of ubiquitinylation is the presence of multiple types of Ub-Ub linkages in polyubiquitin chains. Ubiquitin (Ub) is attached, via isopeptide bonds, to lysine residues in the target protein. These Ub-moieties can then serve as substrates for the conjugation of additional Ubs, again through the formation of isopeptide bonds between the C- terminus of one Ub and any of seven (7) lysines in the target Ub. The general consensus in the field is that chains with different linkages
convey different meanings to the cell and hence, determine the ultimate fate of the protein, be it degradation, translocation, phosphorylation, etc. The precise information encoded in different chain linkages is largely unknown due to the lack of specific reagents that recognize different linkages. The goal of this proposal is to develop tools that allow the selective identification, quantification, and isolation of proteins modified by polyubiquitin chains containing different linkages. This will be accomplished using information encoded in the human genome that allows the cell to discriminate between different linkages, i.e. Ub-binding domains (UbDs). In Phase I, we will identify and characterize novel UbDs exhibiting, at least, partial selectivity. In Phase II we will use these UbDs to construct higher avidity reagents capable of linkage-specific discrimination. Both ubiquitinylation and de- ubiquitinylation have been linked to cancer, inflammation and neurological diseases; hence, the tools developed in this grant will have a major impact on our ability to dissect these disease processes.
PUBLIC HEALTH RELEVANCE: Ubiquitinylation and de-ubiquitinylation are post-translational modifications that affect the function of many proteins and whose dysregulation has been implicated in many disease processes from cancer to inflammation to neurological degeneration. Study of these modifications is difficult due to their low abundance and the complexity of polyubiquitin chains. This grant proposes to generate specific reagents that will distinguish between different forms of polyubiquitin, enabling their detection and isolation from complex mixtures. Use of these tools will dramatically enhance our understanding of many diseases.
描述(由申请人提供):从复杂混合物中对低丰度蛋白的识别,定量和隔离充其量是一项艰巨的任务。尤其是这样
用于携带翻译后修饰(PTM)的蛋白质,影响其半衰期或调节性能。这种PTM的实例包括磷酸化,糖基化(尤其是O-Glcnacylation)和泛素化。在许多情况下,一个PTM可以在同一蛋白质上消除或增强其他PTM,从而提供精致的机制来控制蛋白质活性。如果没有选择性工具,“钓鱼”可能是一种特定的PTM蛋白质,几乎是不可能的。在泛素化的情况下,进一步的并发症是多种类型的ub-ub链接存在多泛素链中。泛素(UB)通过异肽键连接到靶蛋白中的赖氨酸残基。然后,这些UB-Moieties可以通过在一个UB的C末端和目标UB中的七(7)个赖氨酸中的任何一个中形成异肽键,作为额外瑞银结合的底物。该领域的一般共识是具有不同联系的链条
向细胞传达不同的含义,因此,确定蛋白质的最终命运,无论是降解,易位,磷酸化等。不同链条链接中编码的精确信息在很大程度上是未知的,这在很大程度上是未知的。该提案的目的是开发工具,以允许选择性识别,定量和隔离蛋白质,该蛋白质通过包含不同链接的多泛素链修饰的蛋白质。这将使用人类基因组中编码的信息来完成,该信息允许细胞区分不同的链接,即UB结合域(UBD)。在第一阶段,我们将识别并表征具有部分选择性的新型UBD。在第二阶段,我们将使用这些UBD来构建能够特定于连锁歧视的较高的亲发试剂。泛素化和泛素化蛋白化都与癌症,炎症和神经系统疾病有关。因此,这笔赠款中开发的工具将对我们剖析这些疾病过程的能力产生重大影响。
公共卫生相关性:泛素化和去泛素化是翻译后修饰,会影响许多蛋白质的功能,并且其失调与从癌症到炎症到神经系统变性的许多疾病过程有关。由于它们的丰度低和多泛素链的复杂性,对这些修饰的研究很困难。该赠款建议生成特定的试剂,以区分不同形式的多泛素,从而使它们的检测和从复杂混合物中分离出来。这些工具的使用将极大地增强我们对许多疾病的理解。
项目成果
期刊论文数量(0)
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数据更新时间:2024-06-01
James Strickler的其他基金
Development of linkage-specific ubiquitin binding elements
连锁特异性泛素结合元件的开发
- 批准号:88341968834196
- 财政年份:2014
- 资助金额:$ 19.95万$ 19.95万
- 项目类别:
Development of linkage-specific ubiquitin binding elements
连锁特异性泛素结合元件的开发
- 批准号:89309238930923
- 财政年份:2014
- 资助金额:$ 19.95万$ 19.95万
- 项目类别:
Identification and characterization of linkage-specific ubiquitin binding element
连接特异性泛素结合元件的鉴定和表征
- 批准号:85491738549173
- 财政年份:2012
- 资助金额:$ 19.95万$ 19.95万
- 项目类别:
Dissecting ubiquitin pathway selectivity with Ub-isopeptide microarrays
使用 Ub 异肽微阵列剖析泛素通路选择性
- 批准号:79942527994252
- 财政年份:2010
- 资助金额:$ 19.95万$ 19.95万
- 项目类别:
A novel fluorescent assay for ubiquitin isopeptide bond cleavage
泛素异肽键裂解的新型荧光测定
- 批准号:84361868436186
- 财政年份:2010
- 资助金额:$ 19.95万$ 19.95万
- 项目类别:
A novel fluorescent assay for ubiquitin isopeptide bond cleavage
泛素异肽键裂解的新型荧光测定
- 批准号:82001318200131
- 财政年份:2010
- 资助金额:$ 19.95万$ 19.95万
- 项目类别:
SUMO fusion technology for eukaryotic protein expression systems
真核蛋白表达系统的 SUMO 融合技术
- 批准号:74819307481930
- 财政年份:2008
- 资助金额:$ 19.95万$ 19.95万
- 项目类别:
Biomarker Discovery: Ubiquitin Pathway Protein Microarrays
生物标志物发现:泛素通路蛋白质微阵列
- 批准号:81352128135212
- 财政年份:2007
- 资助金额:$ 19.95万$ 19.95万
- 项目类别:
Biomarker Discovery: Ubiquitin Pathway Protein Microarrays
生物标志物发现:泛素通路蛋白质微阵列
- 批准号:79399397939939
- 财政年份:2007
- 资助金额:$ 19.95万$ 19.95万
- 项目类别:
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