Allosteric linkers in cAMP signalling
Allosteric linkers in cAMP signalling
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DOI：
10.1042/bst20130257
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发表时间：
2014-02-01
影响因子：
3.9
通讯作者：
Melacini, Giuseppe
中科院分区：
文献类型：
--
作者：
Akimoto, Madoka;Moleschi, Kody;Melacini, Giuseppe
由动态连接体介导的弱相互作用是多结构域信号蛋白变构调节的关键决定因素。然而，连接依赖控制的机制在很大程度上仍然难以捉摸。在本文中，我们回顾了最近引入的一种变构模型，该模型解释了信号蛋白如何有效地感知和响应弱相互作用，例如由球状结构域两侧的柔性连接体引起的弱相互作用。该模型的核心思想是，在构象选择的自由能范围内，近简并最大限度地放大了对弱（类似于2RT）但构象选择性相互作用的响应。该模型使用蛋白激酶A的原型调节亚基(R)作为原理证明进行了测试，并导致了意想不到的发现，即动态连接体通过调节最小填充中间体（载脂蛋白R）的抑制预平衡来控制激酶的激活和抑制。提出的模型的一个实际意义是设计激酶抑制剂的新策略，通过减轻挫折的突变增强效力。
Weak interactions mediated by dynamic linkers are key determinants of allosteric regulation in multidomain signalling proteins. However, the mechanisms of linker-dependent control have remained largely elusive. In the present article, we review an allosteric model introduced recently to explain how signalling proteins effectively sense and respond to weak interactions, such as those elicited by flexible linkers flanking globular domains. Central to this model is the idea that near degeneracy within the free energy landscape of conformational selection maximally amplifies the response to weak (similar to 2RT), but conformation-selective interactions. The model was tested as proof of principle using the prototypical regulatory subunit (R) of protein kinase A and led to the unanticipated finding that dynamic linkers control kinase activation and inhibition by tuning the inhibitory pre-equilibrium of a minimally populated intermediate (apo R). A practical implication of the proposed model is a new strategy to design kinase inhibitors with enhanced potency through frustration-relieving mutations.