UNDERSTANDING THE FUNCTION OF DEUBIQUITINASES USING CHEMICAL TOOLS
使用化学工具了解去泛素酶的功能
基本信息
- 批准号:8674033
- 负责人:
- 金额:$ 28.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-08-01 至 2019-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressBindingBiochemicalBiologicalBiological AssayBiologyC-terminalCellsCellular biologyCervicalChemicalsCleaved cellCollectionComplementDataDeubiquitinating EnzymeDevelopmentDrug TargetingEnzymesEsophagealEukaryotic CellEventExcisionFamilyFoundationsGoalsHeart DiseasesHepatocyteHuman GenomeHydrolaseInvestigationKineticsKnowledgeLaboratoriesLeadLysineMalignant NeoplasmsMapsMass Spectrum AnalysisMeasuresMethodsModelingModificationMolecularNMR SpectroscopyNatureNeurodegenerative DisordersOutcomePathway interactionsPharmaceutical PreparationsPhasePhysiologicalPlayPost-Translational Protein ProcessingProcessPropertyProteinsReagentRegulationResearchRoentgen RaysRoleScienceSignal PathwaySignal TransductionSite-Directed MutagenesisStructure-Activity RelationshipTechniquesTestingTherapeutic InterventionTransforming Growth FactorsTranslatingUbiquitinVariantWorkX-Ray Crystallographyadductcell motilitydesignfightinghuman diseaseinformation processinginsightmembermolecular dynamicsnervous system disorderprogramsprotein functionpublic health relevanceresponsetooltumortumorigenesisubiquitin C-terminal hydrolaseubiquitin ligase
项目摘要
DESCRIPTION (provided by applicant): The human genome encodes approximately 100 deubiquitinating enzymes (also known as DUBs). These enzymes regulate a broad swath of cell and organismal biology by removing the small protein ubiquitin (Ub) from target proteins or trimming Ub oligomers. Despite the importance of DUBs, there are fundamental gaps in our knowledge regarding how they work. The family of DUBs known as the Ub C-terminal hydrolases (UCHs) embodies this situation. Biochemical data suggests UCHs catalyze the removal of small C-terminal adducts from Ub, whereas data from cellular studies implicates these enzymes in the disassembly of Ub oligomers. Recently, our laboratory developed a straightforward chemical approach towards the synthesis of a wide array of ubiquitin oligomers. Using these oligomers to probe the function of DUBs, we discovered two members of the UCH family, UCH37 and UCHL3, selectively hydrolyze Ub chains in which a single Ub subunit is modified with two Ub molecules through two lysine residues (herein referred to as branched Ub chains). This activity is unprecedented, as the capacity of UCH37 and UCHL3 to dismantle other defined Ub oligomers has not been observed and the function of branched Ub chains is entirely unknown. Considering the importance of UCHL3 and UCH37 in cellular differentiation, development, and motility, our results suggest branched Ub chains play far more important roles in biology than ever appreciated. In this application, we propose to uncover the mechanism by which UCHs selectively hydrolyze branched Ub chains and test this activity in the context of a pathway regulated by UCH37. The proposed work is divided into three specific aims. In the first aim, we will expand the repertoire of chemically synthesized Ub chains to investigate the kinetics and selectivity of chain disassembly. In the second aim, we will structurally characterize
branched Ub chains and their interactions with UCHs. Together with the studies proposed in aim 1, these investigations will lead to working model for the function of UCH37 and UCHL3. In aim 3, we will put this model to the test with regards to UCH37. A number of tumors (e.g., cervical, hepatocellular, and esophageal) display abnormally high levels of UCH37. We hypothesize that UCH37 promotes tumorigenesis by disrupting a critical regulator of cellular migration, i.e., branched Ub chains. The mechanistic insights gained from our proposed studies have excellent potential to be translated into the development of new drugs to fight cancer.
描述(由申请人提供):人类基因组编码约100种去泛素化酶(也称为DUB)。这些酶通过从靶蛋白中去除小蛋白泛素(Ub)或修剪Ub寡聚体来调节广泛的细胞和生物学。尽管DUBs很重要,但我们对它们如何工作的了解存在根本性的差距。被称为Ub C-末端水解酶(UCH)的DUB家族体现了这种情况。生化数据表明,UCH催化去除小的C-末端加合物从Ub,而从细胞研究的数据暗示这些酶在Ub寡聚体的解体。最近,我们的实验室开发了一种简单的化学方法,合成了大量的泛素低聚物。使用这些寡聚体来探测DUB的功能,我们发现UCH家族的两个成员UCH 37和UCHL 3选择性地水解Ub链,其中单个Ub亚基通过两个赖氨酸残基被两个Ub分子修饰(本文称为分支Ub链)。这种活性是前所未有的,因为尚未观察到UCH 37和UCHL 3拆除其他定义的Ub寡聚体的能力,并且分支Ub链的功能完全未知。考虑到UCHL 3和UCH 37在细胞分化、发育和运动中的重要性,我们的研究结果表明分支Ub链在生物学中发挥的作用比以往任何时候都要重要。在本申请中,我们建议揭示UCH选择性水解分支Ub链的机制,并在UCH 37调节的途径中测试这种活性。拟议的工作分为三个具体目标。在第一个目标中,我们将扩大化学合成的Ub链的库,以研究链分解的动力学和选择性。在第二个目标中,我们将从结构上描述
分支Ub链及其与UCH的相互作用。这些研究与目标1中提出的研究一起,将导致UCH 37和UCHL 3功能的工作模型。在目标3中,我们将针对UCH 37对该模型进行测试。许多肿瘤(例如,宫颈、肝细胞和食道)显示出异常高水平的UCH 37。我们假设UCH 37通过破坏细胞迁移的关键调节因子,即,分支的Ub链。从我们提出的研究中获得的机制见解具有很好的潜力,可以转化为抗癌新药的开发。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ERIC Robert STRIETER其他文献
ERIC Robert STRIETER的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ERIC Robert STRIETER', 18)}}的其他基金
Defining the Function of Proteasomal Deubiquitinases
定义蛋白酶体去泛素酶的功能
- 批准号:
10623537 - 财政年份:2023
- 资助金额:
$ 28.15万 - 项目类别:
Chemistry-Biology Interface Predoctoral Training Grant
化学-生物界面博士前培训补助金
- 批准号:
10410350 - 财政年份:2021
- 资助金额:
$ 28.15万 - 项目类别:
Chemistry-Biology Interface Predoctoral Training Grant
化学-生物界面博士前培训补助金
- 批准号:
10618976 - 财政年份:2021
- 资助金额:
$ 28.15万 - 项目类别:
Chemistry-Biology Interface Predoctoral Training Grant
化学-生物界面博士前培训补助金
- 批准号:
10090023 - 财政年份:2021
- 资助金额:
$ 28.15万 - 项目类别:
DEFINING THE FUNCTION OF PROTEASOMAL DEUBIQUITINASES
定义蛋白酶体去泛素酶的功能
- 批准号:
10454952 - 财政年份:2014
- 资助金额:
$ 28.15万 - 项目类别:
DEFINING THE FUNCTION OF PROTEASOMAL DEUBIQUITINASES
定义蛋白酶体去泛素酶的功能
- 批准号:
10221698 - 财政年份:2014
- 资助金额:
$ 28.15万 - 项目类别:
Understanding the Function of Deubiquitinases Using Chemical Tools: Administrative Supplement
使用化学工具了解去泛素酶的功能:行政补充
- 批准号:
9895355 - 财政年份:2014
- 资助金额:
$ 28.15万 - 项目类别:
Understanding the Function of Deubiquitinases Using Chemical Tools
使用化学工具了解去泛素酶的功能
- 批准号:
9262253 - 财政年份:2014
- 资助金额:
$ 28.15万 - 项目类别:
Understanding the Function of Deubiquitinases Using Chemical Tools
使用化学工具了解去泛素酶的功能
- 批准号:
9381472 - 财政年份:2014
- 资助金额:
$ 28.15万 - 项目类别:
相似国自然基金
帽结合蛋白(cap binding protein)调控乙烯信号转导的分子机制
- 批准号:32170319
- 批准年份:2021
- 资助金额:58.00 万元
- 项目类别:面上项目
帽结合蛋白(cap binding protein)调控乙烯信号转导的分子机制
- 批准号:
- 批准年份:2021
- 资助金额:58 万元
- 项目类别:
ID1 (Inhibitor of DNA binding 1) 在口蹄疫病毒感染中作用机制的研究
- 批准号:31672538
- 批准年份:2016
- 资助金额:62.0 万元
- 项目类别:面上项目
番茄EIN3-binding F-box蛋白2超表达诱导单性结实和果实成熟异常的机制研究
- 批准号:31372080
- 批准年份:2013
- 资助金额:80.0 万元
- 项目类别:面上项目
P53 binding protein 1 调控乳腺癌进展转移及化疗敏感性的机制研究
- 批准号:81172529
- 批准年份:2011
- 资助金额:58.0 万元
- 项目类别:面上项目
DBP(Vitamin D Binding Protein)在多发性硬化中的作用和相关机制的蛋白质组学研究
- 批准号:81070952
- 批准年份:2010
- 资助金额:35.0 万元
- 项目类别:面上项目
研究EB1(End-Binding protein 1)的癌基因特性及作用机制
- 批准号:30672361
- 批准年份:2006
- 资助金额:24.0 万元
- 项目类别:面上项目
相似海外基金
Biochemical characterization of an inflammation related protein, mTOC (Celastramycin binding protein)
炎症相关蛋白 mTOC(西拉霉素结合蛋白)的生化特征
- 批准号:
17K07346 - 财政年份:2017
- 资助金额:
$ 28.15万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Characterization of the impact of Arginine Methylation of RNA Binding Proteins on Their Biochemical
RNA 结合蛋白精氨酸甲基化对其生化影响的表征
- 批准号:
511321-2017 - 财政年份:2017
- 资助金额:
$ 28.15万 - 项目类别:
University Undergraduate Student Research Awards
Biochemical & Genetic Analysis of Low Complexity Domains in RNA-binding protein biology
生化
- 批准号:
9335978 - 财政年份:2016
- 资助金额:
$ 28.15万 - 项目类别:
Biochemical & Genetic Analysis of Low Complexity Domains in RNA-binding protein biology
生化
- 批准号:
9158657 - 财政年份:2016
- 资助金额:
$ 28.15万 - 项目类别:
EAGER: Biochemical Mechanism of Oomycete RXLR Effector Binding to PI3P
EAGER:卵菌 RXLR 效应子与 PI3P 结合的生化机制
- 批准号:
1449122 - 财政年份:2014
- 资助金额:
$ 28.15万 - 项目类别:
Standard Grant
Biochemical analysis of plant calcium-binding proteins
植物钙结合蛋白的生化分析
- 批准号:
448832-2013 - 财政年份:2013
- 资助金额:
$ 28.15万 - 项目类别:
University Undergraduate Student Research Awards
Genetic and biochemical analysis of the CaMK family of calmodulin-binding kinases in root and nodule function of Glycine max and Medicago truncatula
钙调蛋白结合激酶 CaMK 家族在大豆和蒺藜苜蓿根和根瘤功能中的遗传和生化分析
- 批准号:
409766-2011 - 财政年份:2013
- 资助金额:
$ 28.15万 - 项目类别:
Postgraduate Scholarships - Doctoral
Genetic and biochemical analysis of the CaMK family of calmodulin-binding kinases in root and nodule function of Glycine max and Medicago truncatula
钙调蛋白结合激酶 CaMK 家族在大豆和蒺藜苜蓿根和根瘤功能中的遗传和生化分析
- 批准号:
409766-2011 - 财政年份:2012
- 资助金额:
$ 28.15万 - 项目类别:
Postgraduate Scholarships - Doctoral
Biochemical, cellular and molecular studies to dissect the contribution of the soluble host carbohydrate binding proteins to HIV-1 pathogenesis
生化、细胞和分子研究,剖析可溶性宿主碳水化合物结合蛋白对 HIV-1 发病机制的贡献
- 批准号:
239201 - 财政年份:2011
- 资助金额:
$ 28.15万 - 项目类别:
Operating Grants
Genetic and biochemical analysis of the CaMK family of calmodulin-binding kinases in root and nodule function of Glycine max and Medicago truncatula
钙调蛋白结合激酶 CaMK 家族在大豆和蒺藜苜蓿根和根瘤功能中的遗传和生化分析
- 批准号:
409766-2011 - 财政年份:2011
- 资助金额:
$ 28.15万 - 项目类别:
Postgraduate Scholarships - Doctoral