The Role of Highwire/DFsn Ubiquitination Complex During Synaptic Development

Highwire/DFsn 泛素化复合物在突触发育过程中的作用

基本信息

  • 批准号:
    7944601
  • 负责人:
  • 金额:
    $ 31.06万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-07-01 至 2015-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Ubiquitination is a key regulatory mechanism for synaptic development, signaling, and plasticity. The covalent attachment of the 76 aa peptide ubiquitin to target proteins is a rapid and reversible modification that regulates protein stability, activity and localization. As such, it is a potent mechanism for sculpting the synapse. We have uncovered a ubiquitination complex composed of the E3 ubiquitin ligase Highwire (Hiw) and the F-Box protein DFsn that plays a central role in controlling synaptic growth and function at the Drosophila neuromuscular junction (NMJ). A highly homologous ubiquitination complex has also been identified in the mammalian brain, where it plays a critical role in regulating axon guidance and synaptogenesis. However, the molecular architecture and molecular action of this ubiquitination complex is not well understood. We propose that Hiw and DFsn form a non-SCF ubiquitin complex where Hiw functions as an E3 ligase and a scaffolding protein to facilitate multi-subunit interaction, and the combination of different co-factors and ubiquitin substrates confers time- and cell type-specific regulation of neuronal functions. Thus identifying other components and novel ubiquitin targets of this ubiquitination complex is key to understanding how the hiw-mediated ubiquitin pathway specifically regulates synaptic development. We have taken two independent approaches to address this question. Biochemically, we identified Hiw/DFsn interacting proteins through tandem affinity purification using fly brains that express affinity-tagged Hiw and DFsn proteins, respectively. Studying the role of two of the Hiw- binding proteins, NSF and Rae1, in synaptic development (aim1), and how they work together with Hiw and DFsn to modulate the ubiquitin ligase activity (aim2) will define an essential ubiquitination machinery that controls synaptic growth. Genetically, we identified 5 hiw enhancer complementation groups through a hiw enhancer screen. Studying these genetic hiw interactors will allow us to identify other molecular pathways that work together with the Hiw/DFsn ubiquitin pathway to shape the structure and strength of synaptic connections formed during development (aim3). PUBLIC HEALTH RELEVANCE: The results of this project will improve our understanding of how nerve cells make connections with other nerve and muscle cells during development. If these connections do not form or function properly in children, it may lead to neurological diseases such as mental retardation, epilepsy, and autism; in addition, if we know how to stimulate these nerve cells to make new appropriate connections we may, in the future, put normal nerve cells back to our nervous system to treat traumatic spinal cord injuries and neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Thus an understanding of the molecules that control the formation and function of nerve cell connections could aid in the future development of new therapies for devastating neurological diseases.
描述(由申请人提供):泛素化是突触发育、信号传导和可塑性的关键调节机制。76 aa肽泛素与靶蛋白的共价连接是一种快速和可逆的修饰,其调节蛋白质的稳定性、活性和定位。因此,它是塑造突触的有效机制。我们已经发现了一种泛素化复合物,由E3泛素连接酶Highwire(Hiw)和F-Box蛋白DFsn组成,在控制果蝇神经肌肉接头(NMJ)的突触生长和功能中起着核心作用。在哺乳动物脑中也发现了一种高度同源的泛素化复合物,它在调节轴突导向和突触发生中起着关键作用。然而,这种泛素化复合物的分子结构和分子作用还不清楚。我们建议,Hiw和DFsn形成一个非SCF泛素复合物,其中Hiw作为E3连接酶和支架蛋白的功能,以促进多亚基相互作用,不同的辅因子和泛素底物的组合赋予神经元功能的时间和细胞类型特异性调节。因此,识别这种泛素化复合物的其他成分和新的泛素靶点是理解hiw-mediated泛素途径如何特异性调节突触发育的关键。 我们采取了两种独立的方法来解决这个问题。生物化学,我们确定了Hiw/DFsn相互作用的蛋白质,通过串联亲和纯化使用苍蝇的大脑,表达亲和标记的Hiw和DFsn蛋白,分别。研究两种Hiw结合蛋白NSF和Rae 1在突触发育(aim 1)中的作用,以及它们如何与Hiw和DFsn一起调节泛素连接酶活性(aim 2),将确定控制突触生长的基本泛素化机制。在遗传学上,我们通过hiw增强子筛选确定了5个hiw增强子互补组。研究这些遗传hiw相互作用将使我们能够确定与Hiw/DFsn泛素途径一起工作的其他分子途径,以塑造发育过程中形成的突触连接的结构和强度(aim 3)。 公共卫生关系:该项目的结果将提高我们对神经细胞在发育过程中如何与其他神经和肌肉细胞连接的理解。如果这些连接在儿童身上不能正常形成或发挥作用,可能会导致精神发育迟滞、癫痫、自闭症等神经系统疾病;此外,如果我们知道如何刺激这些神经细胞,使新的适当的连接,我们可能会在未来,把正常的神经细胞回到我们的神经系统,以治疗创伤性脊髓损伤和神经退行性疾病,如阿尔茨海默病和帕金森病。因此,对控制神经细胞连接的形成和功能的分子的理解可能有助于未来开发针对毁灭性神经疾病的新疗法。

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 }}

Chunlai Wu其他文献

Chunlai Wu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('Chunlai Wu', 18)}}的其他基金

Wrd promotes active zone stability through dephosphorylation of Coracle
Wrd 通过 Coracle 去磷酸化促进活性区稳定性
  • 批准号:
    10811227
  • 财政年份:
    2023
  • 资助金额:
    $ 31.06万
  • 项目类别:
Enhancing Mask/ANKHD1 activity to protect against Tau-induced neurodegeneration
增强 Mask/ANKHD1 活性以预防 Tau 诱导的神经变性
  • 批准号:
    10288299
  • 财政年份:
    2021
  • 资助金额:
    $ 31.06万
  • 项目类别:
Wrd-specific PP2A substrates that regulate AZ stability
调节 AZ 稳定性的 Wrd 特异性 PP2A 底物
  • 批准号:
    9137739
  • 财政年份:
    2015
  • 资助金额:
    $ 31.06万
  • 项目类别:
The Role of Highwire/DFsn Ubiquitination Complex During Synaptic Development
Highwire/DFsn 泛素化复合物在突触发育过程中的作用
  • 批准号:
    8467765
  • 财政年份:
    2010
  • 资助金额:
    $ 31.06万
  • 项目类别:
The Role of Highwire/DFsn Ubiquitination Complex During Synaptic Development
Highwire/DFsn 泛素化复合物在突触发育过程中的作用
  • 批准号:
    8271401
  • 财政年份:
    2010
  • 资助金额:
    $ 31.06万
  • 项目类别:
The Role of Highwire/DFsn Ubiquitination Complex During Synaptic Development
Highwire/DFsn 泛素化复合物在突触发育过程中的作用
  • 批准号:
    8066970
  • 财政年份:
    2010
  • 资助金额:
    $ 31.06万
  • 项目类别:
The Role of Highwire/DFsn Ubiquitination Complex During Synaptic Development
Highwire/DFsn 泛素化复合物在突触发育过程中的作用
  • 批准号:
    8672700
  • 财政年份:
    2010
  • 资助金额:
    $ 31.06万
  • 项目类别:

相似海外基金

Cellular membrane affinity chromatography kit for drug discovery
用于药物发现的细胞膜亲和层析试剂盒
  • 批准号:
    10506915
  • 财政年份:
    2021
  • 资助金额:
    $ 31.06万
  • 项目类别:
Cellular membrane affinity chromatography kit for drug discovery
用于药物发现的细胞膜亲和层析试剂盒
  • 批准号:
    10325006
  • 财政年份:
    2021
  • 资助金额:
    $ 31.06万
  • 项目类别:
SBIR Phase I: A New Class of Immobilized Metal Affinity Chromatography Resins
SBIR 第一阶段:一类新型固定金属亲和色谱树脂
  • 批准号:
    1746198
  • 财政年份:
    2018
  • 资助金额:
    $ 31.06万
  • 项目类别:
    Standard Grant
Marine speciation of nickel using immobilized nickel affinity chromatography
使用固定镍亲和色谱法测定镍的海洋形态
  • 批准号:
    512537-2017
  • 财政年份:
    2017
  • 资助金额:
    $ 31.06万
  • 项目类别:
    University Undergraduate Student Research Awards
I-Corps: Commercialization of Immobilized Metal Affinity Chromatography Resins Based on Nanomaterials
I-Corps:基于纳米材料的固定化金属亲和层析树脂的商业化
  • 批准号:
    1404605
  • 财政年份:
    2014
  • 资助金额:
    $ 31.06万
  • 项目类别:
    Standard Grant
Antibody Purification via Affinity Chromatography that Utilizes the Unconventional Nucleotide Binding Site
利用非常规核苷酸结合位点通过亲和色谱法纯化抗体
  • 批准号:
    1263713
  • 财政年份:
    2013
  • 资助金额:
    $ 31.06万
  • 项目类别:
    Continuing Grant
Development of multivalent DNA network based affinity chromatography diagnostics for isolating circulating tumour cells
开发基于多价 DNA 网络的亲和色谱诊断法,用于分离循环肿瘤细胞
  • 批准号:
    425749-2012
  • 财政年份:
    2012
  • 资助金额:
    $ 31.06万
  • 项目类别:
    Postgraduate Scholarships - Master's
Next-Generation Affinity Chromatography with PEGylated Ligands
使用聚乙二醇化配体的新一代亲和色谱法
  • 批准号:
    1159886
  • 财政年份:
    2012
  • 资助金额:
    $ 31.06万
  • 项目类别:
    Standard Grant
Immobilized zirconium ion affinity chromatography for specific enrichment of phosphoproteins
用于磷蛋白特异性富集的固定化锆离子亲和层析
  • 批准号:
    19560760
  • 财政年份:
    2007
  • 资助金额:
    $ 31.06万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Accelerating drug discovery using frontal affinity chromatography/mass spectrometry
使用正面亲和色谱/质谱加速药物发现
  • 批准号:
    234753-2000
  • 财政年份:
    2003
  • 资助金额:
    $ 31.06万
  • 项目类别:
    Collaborative Research and Development Grants
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了