不同靶点对钙调素叶的调节：半集中构象转变的变构模型
Modulation of calmodulin lobes by different targets: an allosteric model with hemiconcerted conformational transitions
摘要：
钙调素是真核生物中普遍存在的钙激活的第二信使，是一种非常通用的分子，参与许多生物学过程：肌肉收缩、突触可塑性、昼夜节律和细胞周期等。该蛋白质在结构上被组织成两个球状裂片，由柔性接头连接。钙调节钙调蛋白的活性，有利于从一个封闭的构象到一个开放的构象每个叶的构象转变。大多数靶标对一种构象具有强烈的偏好，并且取决于细胞中的游离钙浓度，特定的靶标组将优先与钙调蛋白相互作用。反过来，靶点可以增加或降低它们所结合的钙调蛋白分子的钙亲和力。有趣的是，用胰蛋白酶片段进行的实验表明，大多数靶标对N端的亲和力远低于对C端的亲和力。因此，后者在大多数钙调素-靶复合物的形成中占主导地位。我们发现，一个相对简单的变构机制，经典的MWC模型的基础上，可以捕捉到观察到的调制孤立的C-叶，和完整的钙调素，由个别目标。此外，我们的模型可以自然地扩展到研究一个单一的钙调蛋白池的钙亲和力是如何调制的竞争目标在体内的混合物。
英文摘要：
Calmodulin, the ubiquitous calcium-activated second messenger in eukaryotes, is an extremely versatile molecule involved in many biological processes: muscular contraction, synaptic plasticity, circadian rhythm, and cell cycle, among others. The protein is structurally organised into two globular lobes, joined by a flexible linker. Calcium modulates calmodulin activity by favoring a conformational transition of each lobe from a closed conformation to an open conformation. Most targets have a strong preference for one conformation over the other, and depending on the free calcium concentration in a cell, particular sets of targets will preferentially interact with calmodulin. In turn, targets can increase or decrease the calcium affinity of the calmodulin molecules to which they bind. Interestingly, experiments with the tryptic fragments showed that most targets have a much lower affinity for the N-lobe than for the C-lobe. Hence, the latter predominates in the formation of most calmodulin-target complexes. We showed that a relatively simple allosteric mechanism, based the classic MWC model, can capture the observed modulation of both the isolated C-lobe, and intact calmodulin, by individual targets. Moreover, our model can be naturally extended to study how the calcium affinity of a single pool of calmodulin is modulated by a mixture of competing targets in vivo.
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