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
基本信息
- 批准号:9895355
- 负责人:
- 金额:$ 3.8万
- 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 2019-07-31
- 项目状态:已结题
- 来源:
- 关键词:Administrative SupplementAffectBiochemicalBiologicalBiologyC-terminalCell physiologyCellsChemicalsDataDeubiquitinating EnzymeDevelopmentDrug TargetingEnzymesExcisionFamilyHuman GenomeHydrolaseInvestigationKineticsKnowledgeLaboratoriesLysineMalignant NeoplasmsMass Spectrum AnalysisMethodsModelingModificationNeurodegenerative DisordersPathway interactionsPhysiologicalPlayProteinsRoleStructureTestingTherapeutic InterventionUbiquitinWorkadductbasecell motilitymembertoolubiquitin C-terminal hydrolase
项目摘要
PROJECT SUMMARY
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 by developing
mass spectrometry based methods to detect branched Ub conjugates in cellular
extracts. We hypothesize that aberrant intracellular concentrations of UCHs affect the
homeostatic levels of branched Ub chains, which in turn affects cellular function.
项目总结
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)
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{{ 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:
$ 3.8万 - 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:
$ 3.8万 - 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:
$ 3.8万 - 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:
$ 3.8万 - 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:
$ 3.8万 - 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:
$ 3.8万 - 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:
8674033 - 财政年份:2014
- 资助金额:
$ 3.8万 - 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:
$ 3.8万 - 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:
$ 3.8万 - 项目类别:
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