Computational studies of Arp2/3 activation and deactivation

Arp2/3 激活和失活的计算研究

基本信息

  • 批准号:
    9274331
  • 负责人:
  • 金额:
    $ 5.71万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-06-01 至 2018-05-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Eukaryotic cells depend on actin fibrils to perform a large number of diverse functions, including cell division, adhesion, and movement. Their formation is carefully regulated by the cells, which employ a variety of mechanisms to control polymerization with spatial and temporal specificity. Such a system is governed by a complex network of protein interactions. The importance of this system in cellular function means it has a commensurately large importance in biological malfunction. Mutations in any component can result in genetic disease. Pathogens can also abuse these systems to aid in infection of healthy cells through several pathways. Cancer cell metastasis occurs when cells move themselves away from a tumorous body, and this results from up-regulation of the actin network machinery. A fuller understanding of actin assembly and disassembly is crucial for the treatment of human disease. One of the central components of this system is the actin-related protein complex Arp2/3, which consists of two proteins, Arp2 and Arp3, as well as 5 cofactor proteins ArpC1-5. Arp2/3 binds to a preexisting actin filament and forms the beginnings of a daughter filament, which branches off at a 70º angle. There is evidence that the Arp2/3 complex is by default in an inactive state, i.e.it does not initiate branching without interaction with other cellular components. Conversely, experiments suggest mechanisms that deactivate the complex, promoting debranching. Due to the size and complexity of this protein assembly, relatively few computational studies to date have investigated the Arp2/3 system. I propose to study three aspects of the activation/deactivation of Arp2/3 using computational methodologies to advance our understanding of recent experimental results on these proteins. First, I will study the effect of ion binding at the interface between Arp2/3 and actin. Recent wor suggests that there may be specific sites at the interface where Arp2/3 binds actin to begin a new filament where cations can bind. We will test the hypothesis that having ions in these sites stabilizes the interface and promotes polymerization. Second, I will study the way in which special cofactors called nucleation promoting factors (NPFs) work with Arp2/3 to promote branching by binding Arp2/3 and actin to bring them together and to cause a conformational change in Arp2/3 that allows it to form a good interface with new actin monomers. Third, I will study the effect on Arp2/3 conformation on its ability to transform ATP to ADP, which is one of the controls that promotes debranching. These studies will enhance our understanding at the atomic level of key mechanisms used by cells to control networks of actin fibrils. My work will produce methodological improvements, and my resulting data will aid in the interpretation of previous experiments as well as the design of new ones.
 描述(由申请人提供):真核细胞依赖于肌动蛋白原纤维来执行大量不同的功能,包括细胞分裂、粘附和运动。它们的形成受到细胞的仔细调节,细胞采用多种机制来控制具有空间和时间特异性的聚合。这样的系统由蛋白质相互作用的复杂网络控制。该系统在细胞功能中的重要性意味着它在生物功能障碍中具有非常大的重要性。任何成分的突变都可能导致遗传疾病。病原体也可以通过几种途径滥用这些系统来帮助感染健康细胞。癌细胞转移发生在细胞将自己从肿瘤体中移出时,这是由于肌动蛋白网络机制的上调。更全面地了解肌动蛋白的组装和拆卸对于人类疾病的治疗至关重要。 该系统的核心组成部分之一是肌动蛋白相关蛋白复合物Arp 2/3,它由两种蛋白Arp 2和Arp 3以及5种辅因子蛋白ArpC 1 -5组成。Arp 2/3与预先存在的肌动蛋白丝结合,形成子丝的起点,子丝以70º角分叉。有证据表明Arp 2/3复合物默认处于非活性状态,如果不与其他细胞组分相互作用,则不会启动分支。i.e.it相反,实验表明了使复合物失活的机制,促进了去分支。由于这种蛋白质组装的大小和复杂性,迄今为止相对较少的计算研究已经调查了Arp 2/3系统。我建议研究三个方面的激活/失活Arp 2/3使用计算方法,以促进我们对这些蛋白质的最近的实验结果的理解。 首先,我将研究Arp 2/3和肌动蛋白之间的界面离子结合的效果。最近的研究表明,在Arp 2/3与肌动蛋白结合的界面上可能存在特定的位点,从而开始形成新的微丝,阳离子可在此结合。我们将测试的假设,在这些网站的离子稳定的界面,并促进聚合。第二,我将研究的方式,称为成核促进因子(NPFs)的特殊辅因子与Arp 2/3的工作,以促进分支结合Arp 2/3和肌动蛋白,使他们在一起,并导致在Arp 2/3,使其能够形成一个良好的界面与新的肌动蛋白单体的构象变化。第三,我将研究Arp 2/3构象对其将ATP转化为ADP的能力的影响,ADP是促进脱支的控制之一。 这些研究将增强我们在原子水平上对细胞控制肌动蛋白纤维网络的关键机制的理解。我的工作将产生方法上的改进,我得到的数据将有助于解释以前的实验以及设计新的实验。

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The F-actin bundler α-actinin Ain1 is tailored for ring assembly and constriction during cytokinesis in fission yeast.
  • DOI:
    10.1091/mbc.e16-01-0010
  • 发表时间:
    2016-06-01
  • 期刊:
  • 影响因子:
    3.3
  • 作者:
    Li Y;Christensen JR;Homa KE;Hocky GM;Fok A;Sees JA;Voth GA;Kovar DR
  • 通讯作者:
    Kovar DR
Cations Stiffen Actin Filaments by Adhering a Key Structural Element to Adjacent Subunits.
  • DOI:
    10.1021/acs.jpcb.6b02741
  • 发表时间:
    2016-05-26
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Hocky GM;Baker JL;Bradley MJ;Sinitskiy AV;De La Cruz EM;Voth GA
  • 通讯作者:
    Voth GA
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Glen Hocky其他文献

Glen Hocky的其他文献

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{{ truncateString('Glen Hocky', 18)}}的其他基金

Harnessing simulations to uncover molecular mechanisms of mechanosensing
利用模拟揭示机械传感的分子机制
  • 批准号:
    10648575
  • 财政年份:
    2020
  • 资助金额:
    $ 5.71万
  • 项目类别:
Harnessing simulations to uncover molecular mechanisms of mechanosensing
利用模拟揭示机械传感的分子机制
  • 批准号:
    10727071
  • 财政年份:
    2020
  • 资助金额:
    $ 5.71万
  • 项目类别:
Harnessing simulations to uncover molecular mechanisms of mechanosensing
利用模拟揭示机械传感的分子机制
  • 批准号:
    10028613
  • 财政年份:
    2020
  • 资助金额:
    $ 5.71万
  • 项目类别:
Harnessing simulations to uncover molecular mechanisms of mechanosensing
利用模拟揭示机械传感的分子机制
  • 批准号:
    10450855
  • 财政年份:
    2020
  • 资助金额:
    $ 5.71万
  • 项目类别:
Harnessing simulations to uncover molecular mechanisms of mechanosensing
利用模拟揭示机械传感的分子机制
  • 批准号:
    10247789
  • 财政年份:
    2020
  • 资助金额:
    $ 5.71万
  • 项目类别:
Harnessing simulations to uncover molecular mechanisms of mechanosensing
利用模拟揭示机械传感的分子机制
  • 批准号:
    10467269
  • 财政年份:
    2020
  • 资助金额:
    $ 5.71万
  • 项目类别:
Harnessing simulations to uncover molecular mechanisms of mechanosensing
利用模拟揭示机械传感的分子机制
  • 批准号:
    10652359
  • 财政年份:
    2020
  • 资助金额:
    $ 5.71万
  • 项目类别:
Computational studies of Arp2/3 activation and deactivation
Arp2/3 激活和失活的计算研究
  • 批准号:
    9093581
  • 财政年份:
    2015
  • 资助金额:
    $ 5.71万
  • 项目类别:
Computational studies of Arp2/3 activation and deactivation
Arp2/3 激活和失活的计算研究
  • 批准号:
    8833797
  • 财政年份:
    2015
  • 资助金额:
    $ 5.71万
  • 项目类别:

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    Grant-in-Aid for Challenging Exploratory Research
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