An allosteric model of calmodulin explains differential activation of PP2B and CaMKII
An allosteric model of calmodulin explains differential activation of PP2B and CaMKII
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DOI：
10.1073/pnas.0804672105
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发表时间：
2008-08-05
影响因子：
11.1
通讯作者：
Le Novere, Nicolas
中科院分区：
文献类型：
--
作者：
Stefan, Melanie I.;Edelstein, Stuart J.;Le Novere, Nicolas
钙调素通过在不同钙浓度下激活钙/钙调素依赖的蛋白激酶II(CaMKII)或蛋白磷酸酶2B(PP2B)，在介导双向突触可塑性中发挥重要作用。我们提出了一个钙调蛋白激活的变构模型，在该模型中，与钙的结合促进了低亲和力[紧张(7)]和高亲和力[松弛(R)]状态之间的转换。这四个钙结合位点被认为是不相同的。该模型与之前报道的钙与钙调蛋白结合的实验数据是一致的。这也解释了到目前为止难以建模的钙调蛋白的已知性质，包括不饱和形式的钙调蛋白的活性(我们预测在没有钙的情况下存在开放构象)，一旦钙调蛋白与靶结合，钙亲和力增加，以及CaMKII和PP2B的不同激活取决于钙浓度。
Calmodulin plays a vital role in mediating bidirectional synaptic plasticity by activating either calcium/calmodulin-dependent protein kinase II (CaMKII) or protein phosphatase 2B (PP2B) at different calcium concentrations. We propose an allosteric model for calmodulin activation, in which binding to calcium facilitates the transition between a low-affinity [tense (7)] and a high-affinity [relaxed (R)] state. The four calcium-binding sites are assumed to be nonidentical. The model is consistent with previously reported experimental data for calcium binding to calmodulin. It also accounts for known properties of calmodulin that have been difficult to model so far, including the activity of nonsaturated forms of calmodulin (we predict the existence of open conformations in the absence of calcium), an increase in calcium affinity once calmodulin is bound to a target, and the differential activation of CaMKII and PP2B depending on calcium concentration.