DEFINING THE FUNCTION OF PROTEASOMAL DEUBIQUITINASES
定义蛋白酶体去泛素酶的功能
基本信息
- 批准号:10221698
- 负责人:
- 金额:$ 36.23万
- 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 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:26S proteasomeATP-Dependent ProteasesAddressAffectArchitectureAttentionBindingBiologicalBiological AssayCRISPR/Cas technologyCell LineCellsCellular biologyCleaved cellComplexCrystallographyCyclic PeptidesDataDeubiquitinationDeuteriumDevelopmentDiseaseEmbryoEnzymesFailureFundingGenerationsHealthHumanHuman BiologyHydrogenKineticsKnowledgeLabelLightMalignant NeoplasmsMass Spectrum AnalysisMeasuresMediatingModificationMolecularNeurodegenerative DisordersPathway interactionsPeptide HydrolasesPhage DisplayPhysiologicalPlayPolymersPositioning AttributeProcessProteasome BindingProtein ChemistryProteinsProteomicsResearchRoleSignal TransductionSpecificityStructureSystemTestingTranslationsUbiquitinWorkX-Ray Crystallographycellular targetinggenome editinginhibitor/antagonistinnovationinsightinterdisciplinary approachkidney cellmulticatalytic endopeptidase complexnovelnovel therapeuticsprematurepreventprotein degradationproteostasissmall moleculetherapeutic targettool
项目摘要
Project Summary
The 26S proteasome is a massive, intricately regulated ATP-dependent protease that is responsible for the
degradation of most cellular proteins. Failure of the proteasome to precisely regulate protein levels is a
hallmark of many cancers and neurodegenerative diseases. Targeting proteins to the proteasome requires
covalent modification with a polymeric (Ub) chain. Thus, it is perplexing that the proteasome actually houses
enzymes (deubiquitinases/DUBs) responsible for removing Ub chains. While it has become clear that the
intrinsic DUB, RPN11, promotes degrades by preventing premature deubiquitination of proteins not yet
engaged with the proteasome, the roles of other proteasomal DUBs, e.g., UCH37/UCHL5, are poorly
understood. In preliminary studies, we discovered that proteasome-bound UCH37 acts as a chain editor by
removing branch points. This application proposes to elucidate how UCH37 selects branched Ub chains for
editing, how this activity is integrated into the entire process of proteasomal degradation, and how it impacts
the turnover of cellular proteins. In Aim 1, we will investigate the role of UCH37-mediated chain debranching
during proteasomal degradation using distinct, purified human proteasome complexes and fluorescent,
polyubiquitinated substrates. In Aim 2, we propose to identify cellular targets of proteasome-bound UCH37
using an innovative combination of quantitative proteomics, in-cell proximity labeling, and Ub middle-down
mass spectrometry. In Aim 3, we focus on understanding the molecular basis of UCH37's specificity toward
branched chains. Finally, in Aim 4, we will develop novel cyclic peptide inhibitors of UCH37 to facilitate efforts
to dissect its function in any biological paradigm. The knowledge gained from this research will shed light on
fundamental aspects of the ubiquitin proteasome system and pave the way for the development of new
therapeutics that regulate proteasome function.
项目总结
项目成果
期刊论文数量(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:
$ 36.23万 - 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:
$ 36.23万 - 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:
$ 36.23万 - 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:
$ 36.23万 - 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:
$ 36.23万 - 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:
$ 36.23万 - 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:
$ 36.23万 - 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:
$ 36.23万 - 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:
$ 36.23万 - 项目类别:
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