Expanding Mechanistic Insights into Protein Ubiquitylation

扩展对蛋白质泛素化的机制见解

基本信息

  • 批准号:
    10796652
  • 负责人:
  • 金额:
    $ 9.52万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-08-15 至 2027-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Covalent attachment of ubiquitin (Ub) to other proteins is among the most widespread and diverse modes of eukaryotic cellular regulation. The modification occurs on practically every protein in a cell at some point in its lifetime and is itself highly diverse. The type of ubiquitylation determines a product’s fate and a protein may undergo different modes of ubiquitylation depending on cellular circumstances. The origins of this diversity stem from the protein machinery responsible for Ub attachment. A trio of enzymes, E1, E2, and E3 coordinate the process, with several E1s, dozens of E2s, and many hundreds of E3s encoded in the human genome. Over the past 20 years, we have asked fundamental questions about how E2s and E3s work and have contributed to the structural, biochemical, and mechanistic understandings of the field. Our work began with the breast cancer tumor suppressor, BRCA1/BARD1 that was among the earliest RING-type E3 ligases to be identified. Over the years, we have expanded to study numerous E3s and E2s, making many unexpected discoveries along the way. The wide reach of protein ubiquitylation in cellular function means that dysfunction of components is associated with myriad human diseases and developmental issues. Such associations make the Ub system attractive for therapeutic targeting. Direct targeting of the ubiquitylation machinery as well as efforts to re-engineer protein ubiquitylation machinery to selectively target a specific cellular protein are both proving to be powerful strategies. Such translational efforts rely implicitly on mechanistic understanding and reveal the power of well- grounded structure/function research. Despite the apparent maturity of the field, there is still much we do not understand at a fundamental level. We do not know the full range of biochemical reactions carried out by the ~30 human E2s as fully one-quarter of these are uncharacterized. Existing data reveal that not all E2s carry out the presumed reaction that attaches Ub to lysine sidechains, implying the existence of ubiquitylated species that have yet to be investigated in cells. Second, understanding of how E2/E3s carry out mono-ubiquitylation is lacking. Unlike poly-ubiquitylation, attachment of a single Ub (mono-Ub) tends to occur in a site- selective manner implying that substrates to be mono-ubiquitylated are handled differently from those destined to have chains built upon them. Third, lack of knowledge regarding how mono- Ub attachment affects the structure and function of proteins limits understanding of how the modification regulates critical cellular processes including transcription, translation, and DNA damage response, among others.
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)

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 }}

Rachel E Klevit其他文献

Rachel E Klevit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('Rachel E Klevit', 18)}}的其他基金

Allosteric adhesins of enterobacterial pathogens
肠杆菌病原体的变构粘附素
  • 批准号:
    10512013
  • 财政年份:
    2022
  • 资助金额:
    $ 9.52万
  • 项目类别:
Expanding Mechanistic Insights into Protein Ubiquitylation
扩展对蛋白质泛素化的机制见解
  • 批准号:
    10330645
  • 财政年份:
    2022
  • 资助金额:
    $ 9.52万
  • 项目类别:
Expanding Mechanistic Insights into Protein Ubiquitylation
扩展对蛋白质泛素化的机制见解
  • 批准号:
    10676084
  • 财政年份:
    2022
  • 资助金额:
    $ 9.52万
  • 项目类别:
Allosteric adhesins of enterobacterial pathogens
肠杆菌病原体的变构粘附素
  • 批准号:
    10626963
  • 财政年份:
    2022
  • 资助金额:
    $ 9.52万
  • 项目类别:
Acquisition of Analytical Ultracentrifuge at UW
华盛顿大学购买分析超速离心机
  • 批准号:
    7790426
  • 财政年份:
    2010
  • 资助金额:
    $ 9.52万
  • 项目类别:
Structural and Functional Characterization of BRCA1/BARD1
BRCA1/BARD1 的结构和功能表征
  • 批准号:
    7931268
  • 财政年份:
    2009
  • 资助金额:
    $ 9.52万
  • 项目类别:
Training in Molecular Biophysics
分子生物物理学培训
  • 批准号:
    7883879
  • 财政年份:
    2009
  • 资助金额:
    $ 9.52万
  • 项目类别:
Structure/Function Studies of Small Heat Shock Proteins
小热激蛋白的结构/功能研究
  • 批准号:
    8437511
  • 财政年份:
    2007
  • 资助金额:
    $ 9.52万
  • 项目类别:
Structure/Function Studies of Small Heat Shock Proteins
小热激蛋白的结构/功能研究
  • 批准号:
    7415008
  • 财政年份:
    2007
  • 资助金额:
    $ 9.52万
  • 项目类别:
Mechanisms of Activation for Human Small Heat Shock Proteins: An Integrated Approach
人类小热休克蛋白的激活机制:综合方法
  • 批准号:
    9304219
  • 财政年份:
    2007
  • 资助金额:
    $ 9.52万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了