Miller Paul, Zhabotinsky Anatol M, Lisman John E, Wang Xiao-Jing
Volen Center for Complex Systems, Brandeis University, Waltham, Massachusetts, USA.
PLoS Biol. 2005 Apr;3(4):e107. doi: 10.1371/journal.pbio.0030107. Epub 2005 Mar 29.
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.
分子开关与生物系统中信息的存储有关。对于诸如突触这样的小结构，这些开关仅由少数分子组成，因此随机涨落很重要。这种涨落可能会导致开关自发重置，从而限制信息存储的寿命。我们分析了一种与神经系统长期记忆有关的钙/钙调蛋白依赖性蛋白激酶II（CaMKII）开关模型。这种开关的双稳态源于CaMKII的自催化自磷酸化，而一种可饱和的磷酸酶-1介导的去磷酸化反应会对抗这一反应。我们试图了解控制开关稳定性的因素，并确定稳定性与所涉及分子数量之间的功能关系。通过蒙特卡罗模拟，我们发现开关状态的寿命随CaMKII全酶数量呈指数增加。开关稳定性需要激酶和磷酸酶速率之间的平衡，并且激酶速率相对于蛋白质周转速率必须保持较高。因此，开关稳定性的一个关键限制由观察到的周转速率（平均每30小时一次）设定。我们的计算结果表明，根据酶数量涨落的时间尺度，对于一个由约15个CaMKII全酶组成的开关，稳定的持续激活可以从几年到人类一生不等。
