The stability of a stochastic CaMKII switch: dependence on the number of enzyme molecules and protein turnover.
The stability of a stochastic CaMKII switch: dependence on the number of enzyme molecules and protein turnover.
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DOI：
10.1371/journal.pbio.0030107
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发表时间：
2005-04
期刊：
影响因子：
9.8
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中科院分区：
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分子开关与生物系统中的信息存储有关。对于像突触这样的小结构，这些开关仅由少数分子组成，因此随机波动很重要。这种波动可能会导致自发的开关复位，这将限制信息存储的寿命。我们分析了一个模型的钙/钙调素依赖性蛋白激酶II（CaMKII）开关牵连在神经系统的长期记忆。这种开关的双稳定性源于CaMKII的自催化自磷酸化，这是一种由可饱和磷酸酶-1介导的去磷酸化反应所对抗的反应。我们试图了解控制开关稳定性的因素，并确定稳定性和所涉及的分子数量之间的函数关系。使用Monte Carlo模拟，我们发现，开关的状态的寿命随CaMKII全酶的数量呈指数增长。转换稳定性需要激酶和磷酸酶速率之间的平衡，并且激酶速率必须相对于蛋白质周转速率保持较高。因此，开关稳定性的临界极限由观察到的周转率（平均每30小时一次）设定。我们的计算结果表明，取决于酶数量波动的时间尺度，对于由约15个CaMKII全酶组成的开关，稳定的持续激活可以从几年到一个人的一生。计算模型表明，CaMKII的自磷酸化可以产生持续数年的稳定持续激活
Molecular switches have been implicated in the storage of information in biological systems. For small structures such as synapses, these switches are composed of only a few molecules and stochastic fluctuations are therefore of importance. Such fluctuations could potentially lead to spontaneous switch reset that would limit the lifetime of information storage. We have analyzed a model of the calcium/calmodulin-dependent protein kinase II (CaMKII) switch implicated in long-term memory in the nervous system. The bistability of this switch arises from autocatalytic autophosphorylation of CaMKII, a reaction that is countered by a saturable phosphatase-1-mediated dephosphorylation. We sought to understand the factors that control switch stability and to determine the functional relationship between stability and the number of molecules involved. Using Monte Carlo simulations, we found that the lifetime of states of the switch increase exponentially with the number of CaMKII holoenzymes. Switch stability requires a balance between the kinase and phosphatase rates, and the kinase rate must remain high relative to the rate of protein turnover. Thus, a critical limit on switch stability is set by the observed turnover rate (one per 30 h on average). Our computational results show that, depending on the timescale of fluctuations in enzyme numbers, for a switch composed of about 15 CaMKII holoenzymes, the stable persistent activation can span from a few years to a human lifetime. Computational modeling indicates that autophosphorylation of CaMKII can create stable persistent activation lasting several years