Detailed state model of CaMKII activation and autophosphorylation.
Detailed state model of CaMKII activation and autophosphorylation.
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DOI：
10.1007/s00249-008-0362-4
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发表时间：
2008-11
影响因子：
2
通讯作者：
Kennedy, Mary B.
中科院分区：
文献类型：
--
作者：
Lucic, Vladan;Greif, Gabriela J.;Kennedy, Mary B.
关键词：
通过将生化实验与生化反应的计算机建模相结合，我们阐明了钙钙调素依赖性蛋白激酶II （CaMKII）激活和自磷酸化的一些目前尚未解决的方面，这些方面可能与其生理功能相关，并提供了一个模型，该模型基于实验确定的结合常数和磷酸化速率，详细介绍了CaMKII在T286的激活和自磷酸化机制。为此，我们基于现有文献开发了CaMKII激活和自磷酸化的详细状态模型，并使用CaMKII自磷酸化论文的数据对其进行了限制。我们的模型考虑了CaMKII全酶的精确磷酸化模式，并且在钙和钙调素浓度不饱和的生理相关条件下有效。我们的研究结果强烈表明，即使CaMKII与不完全钙结合的钙调蛋白结合，CaMKII仍处于活性状态，并表明活性的非磷酸化CaMKII亚基对T286的自磷酸化作用明显快于自磷酸化CaMKII亚基。这些结果表明CaMKII可以在比之前认为的低得多的钙浓度下有效激活，这可能解释了CaMKII是如何在体内突触中存在钙浓度时被激活的。我们还研究了CaMKII全酶结构对CaMKII自磷酸化的意义，并获得了以前未知的结合常数的估计。
By combining biochemical experiments with computer modelling of biochemical reactions we elucidated some of the currently unresolved aspects of calcium-calmodulin-dependent protein kinase II (CaMKII) activation and autophosphorylation that might be relevant for its physiological function and provided a model that incorporates in detail the mechanism of CaMKII activation and autophosphorylation at T286 that is based on experimentally determined binding constants and phosphorylation rates. To this end, we developed a detailed state model of CaMKII activation and autophosphorylation based on the currently available literature, and constrained it with data from CaMKII autophosphorylation essays. Our model takes exact phosphorylation patterns of CaMKII holoenzymes into account, and is valid at physiologically relevant conditions where the concentrations of calcium and calmodulin are not saturating. Our results strongly suggest that even when bound to less than fully calcium-bound calmodulin, CaMKII is in the active state, and indicate that the autophosphorylation of T286 by an active non-phosphorylated CaMKII subunit is significantly faster than by an autophosphorylated CaMKII subunit. These results imply that CaMKII can be efficiently activated at significantly lower calcium concentrations than previously thought, which may explain how CaMKII gets activated at calcium concentrations existing at synapses in vivo. We also investigated the significance of CaMKII holoenzyme structure on CaMKII autophosphorylation and obtained estimates of previously unknown binding constants.
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