Molecular computation by the CaMKII holoenzyme

CaMKII 全酶的分子计算

基本信息

  • 批准号:
    10754843
  • 负责人:
  • 金额:
    $ 3.72万
  • 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:
    2022-08-01 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Learning, cognition, and memory require dynamic remodeling of hippocampal synapses, which in turn requires Ca2+/calmodulin-dependent kinase II (CaMKII). CaMKII mediates two opposing modes of synaptic plasticity, long term potentiation (LTP) and depression (LTD), that are induced by distinct Ca2+ stimuli. Both low and high Ca2+ induce CaMKII autophosphorylation (p) at T286, that is required for both LTP and LTD. Additionally, LTP requires CaMKII binding to the NMDA receptor subunit, GluN2B, during high [Ca2+] while LTD requires CaMKII autophosphorylation at T305/306 during low [Ca2+]. Further, these three mechanisms can undergo complex cross-regulation which requires the CaMKII 12-meric holoenzyme. Interestingly, pT286 positively regulates both GluN2B binding and pT305/306 while GluN2B binding and pT305/306 are mutually exclusive. It is unknown how these reactions and interactions are spatiotemporally encoded within holoenzymes and thus how LTP versus LTD signal computation is accomplished by CaMKII. For example, it has been shown that pT286 must occur between two neighboring kinase domains in the holoenzyme. It is still unclear what determines a functional kinase domain neighbor. Moreover, in vitro binding studies have shown that CaMKII holoenzymes are required for binding to GluN2B, suggesting that this interaction may require multiple subunits. Still, it is unknown what is the required stoichiometry and subunit geometry required for CaMKII-GluN2B binding. Initial results suggest that the holoenzyme rules for pT286 and GluN2B binding are fundamentally different. Therefore, this proposal will investigate my hypothesis that LTP versus LTD mechanisms are regulated by structurally distinct features within CaMKII holoenzymes. The approach will utilize several CaMKII “structural mutants” that have disrupted holoenzyme structure (hexamers, dimers, and monomers). These mutants will be used as tools to define the spatiotemporal dynamics of autophosphorylation within holoenzymes and the subunit stoichiometry and geometry required for GluN2B binding. The results of this proposal will provide insight into how molecular signal computation underlying the LTP versus LTD decision is encoded within CaMKII holoenzymes.
项目总结 学习、认知和记忆需要海马体突触的动态重塑,这反过来又需要 钙/钙调蛋白依赖的激酶II(CaMKII)。CaMKII介导两种截然相反的突触可塑性模式 时程增强(LTP)和抑制(LTD),这是由不同的钙离子刺激诱导的。低钙和高钙都有 在T286处诱导CaMKII自动磷酸化(P),这是LTP和LTD都需要的。此外,LTP需要 高[Ca~(2+)]时CaMKII与NMDA受体亚单位GluN2B结合,而LTD需要CaMKII 低[Ca~(2+)]时T305/306的自动磷酸化。此外,这三种机制可能会经历复杂的 交叉调节,这需要CaMKII 12-Meric全酶。有趣的是,pT286正向调节两者 GluN2B结合和pT305/306,而GluN2B结合和pT305/306是互斥的。目前还不清楚是如何做到的 这些反应和相互作用是在全酶中时空编码的,因此LTP与 LTD信号计算由CAMKII完成。例如,已经证明pT286必须发生 在全酶中的两个相邻的激酶结构域之间。目前仍不清楚是什么决定了功能性 激活域的邻居。此外,体外结合研究表明CaMKII全酶是必需的。 与GluN2B结合,表明这种相互作用可能需要多个亚基。尽管如此,什么是未知的 CaMKII-GluN2B结合所需的化学计量比和亚基几何形状。初步结果表明, PT286和GluN2B结合的全酶规则是根本不同的。因此,这项提议将 研究我的假设,即LTP和LTD机制是由 CaMKII全酶。该方法将利用几个已经扰乱了CaMKII的“结构突变” 全酶结构(六聚体、二聚体和单体)。这些突变体将被用作定义 全酶体内自动磷酸化的时空动力学和亚单位化学计量学 GluN2B绑定所需的几何形状。这项提议的结果将提供对分子信号如何 LTP与LTD决定的基础计算编码在CaMKII全酶中。

项目成果

期刊论文数量(0)
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Carolyn Nicole Brown其他文献

Studying CaMKII: Tools and standards
研究钙/钙调蛋白依赖性蛋白激酶II(CaMKII):工具与标准
  • DOI:
    10.1016/j.celrep.2024.113982
  • 发表时间:
    2024-04-23
  • 期刊:
  • 影响因子:
    6.900
  • 作者:
    Carolyn Nicole Brown;Karl Ulrich Bayer
  • 通讯作者:
    Karl Ulrich Bayer

Carolyn Nicole Brown的其他文献

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{{ truncateString('Carolyn Nicole Brown', 18)}}的其他基金

Molecular computation by the CaMKII holoenzyme
CaMKII 全酶的分子计算
  • 批准号:
    10535139
  • 财政年份:
    2022
  • 资助金额:
    $ 3.72万
  • 项目类别:

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