DEFINING THE FUNCTION OF PROTEASOMAL DEUBIQUITINASES

定义蛋白酶体去泛素酶的功能

基本信息

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

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ERIC Robert STRIETER其他文献

ERIC Robert STRIETER的其他文献

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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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ATP依赖性蛋白酶对线粒体基质中的蛋白质质量进行控制
  • 批准号:
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  • 财政年份:
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    2004
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