Intrinsic disorder as a mechanism to optimize allosteric coupling in proteins
Intrinsic disorder as a mechanism to optimize allosteric coupling in proteins
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DOI：
10.1073/pnas.0700329104
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发表时间：
2007-05-15
影响因子：
11.1
通讯作者：
Thompson, E. Brad
中科院分区：
文献类型：
--
作者：
Hilser, Vincent J.;Thompson, E. Brad
转录因子和其他变构细胞信号蛋白包含不成比例数量的结构域或片段，这些结构域或片段在自然条件下是固有的无序(ID)。在许多情况下，这些片段的折叠与它们的一个或多个相互作用伙伴结合在一起，这表明内在无序发挥着重要的功能作用。尽管对ID结构域在调控中的作用提出了许多假说，但还没有建立一个机制模型来定量评估内在无序对分子内点对点通信的重要性，这是变构蛋白的标志性属性。在这里，我们提出了这样一个模型，并表明当包含一个或两个耦合结合位点的结构域或片段中存在本征无序时，点对点变构耦合最大。这一结果不仅解释了调控蛋白中ID结构域的普遍存在，也对经典的蛋白质能量传播力学观点提出了质疑，该观点预测，当一条明确的折叠结构路径连接两个位点时，点对点耦合将最大化。此外，在表明由内在无序引起的耦合机制是强大的并且独立于物理上连接耦合位点的相互作用网络的过程中，我们获得了对支配所有蛋白质中点对点通信的能量基本规则的独特见解。
Transcription factors and other allosteric cell signaling proteins contain a disproportionate number of domains or segments that are intrinsically disordered (ID) under native conditions. in many cases folding of these segments is coupled to binding with one or more of their interaction partners, suggesting that intrinsic disorder plays an important functional role. Despite numerous hypotheses for the role of ID domains in regulation, a mechanistic model has yet to be established that can quantitatively assess the importance of intrinsic disorder for intramolecular site-to-site communication, the hallmark property of allosteric proteins. Here, we present such a model and show that site-to-site allosteric coupling is maximized when intrinsic disorder is present in the domains or segments containing one or both of the coupled binding sites. This result not only explains the prevalence of ID domains in regulatory proteins, it also calls into question the classical mechanical view of energy propagation in proteins, which predicts that site-to-site coupling would be maximized when a well defined pathway of folded structure connects the two sites. Furthermore, in showing that the coupling mechanism conferred by intrinsic disorder is robust and independent of the network of interactions that physically link the coupled sites, unique insights are gained into the energetic ground rules that govern site-to-site communication in all proteins.