Competitive tuning: Competition's role in setting the frequency-dependence of Ca2+-dependent proteins.
Competitive tuning: Competition's role in setting the frequency-dependence of Ca2+-dependent proteins.
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DOI：
10.1371/journal.pcbi.1005820
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发表时间：
2017-11
影响因子：
4.3
通讯作者：
Kinzer-Ursem TL
中科院分区：
文献类型：
--
作者：
Romano DR;Pharris MC;Patel NM;Kinzer-Ursem TL
许多神经系统疾病是由神经元内生化信号传导和蛋白质复合物形成的扰动引起的。通常，蛋白质形成网络，当激活时，突触的分子组成会产生持续的变化。在海马神经元中，钙离子 (Ca2+) 流经 N-甲基-D-天冬氨酸 (NMDA) 受体会激活 Ca2+/钙调蛋白信号转导网络，从而增加或减少神经元突触的强度，这种现象分别称为长时程增强 (LTP) 或长时程抑制 (LTD)。钙传感器钙调蛋白 (CaM) 是负责 LTP 和 LTD 的网络的常见激活剂。这在一定程度上是可能的，因为 CaM 结合蛋白通过其独特的结合和激活动力学“调节”到不同的 Ca2+ 通量信号。计算模型用于描述 Ca2+/CaM 信号转导的结合和激活动力学，可用于指导重点实验研究。尽管 CaM 结合超过 100 种蛋白质，但实际限制导致许多模型仅包含一种或两种 CaM 激活蛋白质。在这项工作中，我们将 Ca2+/CaM 视为信号转导途径中的限制资源，因为其相对于其结合伙伴的丰度较低。基于这一观点，我们研究了竞争性结合对 CaM 结合伴侣激活动态的影响。使用 Ca2+、CaM 和七个高表达的海马 CaM 结合蛋白的显式模型，我们发现 CaM 结合的竞争作为一种调节机制：竞争者的存在改变并加剧了 CaM 结合蛋白的 Ca2+ 频率依赖性。值得注意的是，我们发现模拟竞争可能足以重建 CaM 依赖性磷酸酶钙调神经磷酸酶的体内频率依赖性。此外，单独的竞争（没有反馈机制或空间参数）可以复制神经粒素敲除模型中 Ca2+/CaM 依赖性蛋白激酶 II 激活减少的反直觉实验观察结果。我们得出的结论是，竞争性调节可能是突触可塑性的一个重要动态过程。学习和记忆的形成可能与神经元突触连接强度的动态波动有关。这些波动被称为突触可塑性，由钙离子 (Ca2+) 通过突触后膜局部离子通道的流入来调节。在突触后，主要的 Ca2+ 传感器蛋白钙调蛋白 (CaM) 可能会激活多种下游结合伙伴，每种都有助于突触可塑性结果。人们越来越多地使用计算模型来研究某些结合配偶体最强烈激活的条件。几乎所有计算研究都以仅一种或两种 CaM 结合蛋白的组合来描述这些结合配偶体。相比之下，我们将七个经过充分研究的 CaM 结合伙伴组合到一个模型中，其中它们同时竞争对 CaM 的访问。我们的动态模型表明，竞争缩小了某些结合配偶体最佳激活的条件窗口，模拟了体内某些蛋白质的 Ca2+ 频率依赖性。神经元突触中 CaM 依赖性信号动力学的进一步表征可能有助于我们对学习和记忆形成的理解。此外，我们提出，竞争性结合可能是另一个框架，除了反馈和前馈环路、信号基序和空间定位之外，可以应用于其他信号转导网络，特别是第二信使级联，以解释蛋白质激活的动态行为。
A number of neurological disorders arise from perturbations in biochemical signaling and protein complex formation within neurons. Normally, proteins form networks that when activated produce persistent changes in a synapse’s molecular composition. In hippocampal neurons, calcium ion (Ca2+) flux through N-methyl-D-aspartate (NMDA) receptors activates Ca2+/calmodulin signal transduction networks that either increase or decrease the strength of the neuronal synapse, phenomena known as long-term potentiation (LTP) or long-term depression (LTD), respectively. The calcium-sensor calmodulin (CaM) acts as a common activator of the networks responsible for both LTP and LTD. This is possible, in part, because CaM binding proteins are “tuned” to different Ca2+ flux signals by their unique binding and activation dynamics. Computational modeling is used to describe the binding and activation dynamics of Ca2+/CaM signal transduction and can be used to guide focused experimental studies. Although CaM binds over 100 proteins, practical limitations cause many models to include only one or two CaM-activated proteins. In this work, we view Ca2+/CaM as a limiting resource in the signal transduction pathway owing to its low abundance relative to its binding partners. With this view, we investigate the effect of competitive binding on the dynamics of CaM binding partner activation. Using an explicit model of Ca2+, CaM, and seven highly-expressed hippocampal CaM binding proteins, we find that competition for CaM binding serves as a tuning mechanism: the presence of competitors shifts and sharpens the Ca2+ frequency-dependence of CaM binding proteins. Notably, we find that simulated competition may be sufficient to recreate the in vivo frequency dependence of the CaM-dependent phosphatase calcineurin. Additionally, competition alone (without feedback mechanisms or spatial parameters) could replicate counter-intuitive experimental observations of decreased activation of Ca2+/CaM-dependent protein kinase II in knockout models of neurogranin. We conclude that competitive tuning could be an important dynamic process underlying synaptic plasticity. Learning and memory formation are likely associated with dynamic fluctuations in the connective strength of neuronal synapses. These fluctuations, called synaptic plasticity, are regulated by calcium ion (Ca2+) influx through ion channels localized to the post-synaptic membrane. Within the post-synapse, the dominant Ca2+ sensor protein, calmodulin (CaM), may activate a variety of downstream binding partners, each contributing to synaptic plasticity outcomes. The conditions at which certain binding partners most strongly activate are increasingly studied using computational models. Nearly all computational studies describe these binding partners in combinations of only one or two CaM binding proteins. In contrast, we combine seven well-studied CaM binding partners into a single model wherein they simultaneously compete for access to CaM. Our dynamic model suggests that competition narrows the window of conditions for optimal activation of some binding partners, mimicking the Ca2+-frequency dependence of some proteins in vivo. Further characterization of CaM-dependent signaling dynamics in neuronal synapses may benefit our understanding of learning and memory formation. Furthermore, we propose that competitive binding may be another framework, alongside feedback and feed-forward loops, signaling motifs, and spatial localization, that can be applied to other signal transduction networks, particularly second messenger cascades, to explain the dynamical behavior of protein activation.
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DOI：
10.1073/pnas.89.10.4363
发表时间：
1992-05-15
影响因子：
11.1
作者：
DUDEK, SM;BEAR, MF
通讯作者：
BEAR, MF
影响因子：
5.7
作者：
Anggono V;Huganir RL
通讯作者：
Huganir RL
影响因子：
5.6
作者：
BABU, YS;BUGG, CE;COOK, WJ
通讯作者：
COOK, WJ
影响因子：
5.5
作者：
Bazzazi, Hojjat;Sang, Lingjie;Yue, David T.
通讯作者：
Yue, David T.
DOI：
10.1073/pnas.87.2.682
发表时间：
1990-01-01
影响因子：
11.1
作者：
BREDT, DS;SNYDER, SH
通讯作者：
SNYDER, SH