Abstract：
Allosteric mechanisms provide finely-tuned control over signalling proteins. Proteins of the same family may share high sequence identity and structural similarity but show distinct traits of allosteric control and evolutionary divergent regulation. Revealing the determinants of such properties may be important to understand the molecular bases of different regulatory pathways. Herein, we investigate whether and how evolutionarily-divergent traits of allosteric regulation in homologous proteins can be decoded in terms of internal dynamics and interaction networks that support functionally oriented conformations. In this framework, we start from the comparative analysis of the dynamics and energetics of the yeast MAP Kinases (MAPKs) Fus3 and Kss1 in their native basins. Importantly, distinctive dynamic and energetic stabilization features emerge, which can be related to the two proteins\' differential ability to be phosphorylated and engage with the allosteric activator Ste5. We then expanded our study to other evolutionarily-related MAPKs. We show that the dynamical and energetical traits defining the distinct regulatory profiles of Fus3 and Kss1 can be traced along their evolutionary tree. Overall, our approach is able to reconnect (latent) allostery with the principal elements of protein structural stabilization and dynamics, showing how allosteric regulation was encrypted in MAPKs structure well before Ste5 appearance.
摘要：
变构机制提供对信号蛋白的精细调节控制。同一家族的蛋白质可能具有高度的序列同一性和结构相似性，但显示出不同的变构控制和进化差异调节特征。揭示这些特性的决定因素对于理解不同调节途径的分子基础可能很重要。在这里，我们研究了同源蛋白质中变构调节的进化差异特征是否以及如何可以根据支持功能定向构象的内部动力学和相互作用网络进行解码。在这个框架中,我们从酵母MAP激酶（MAPKs）Fus3和Kss1在其天然盆地中的动力学和能量学的比较分析开始。重要的是,出现了独特的动态和能量稳定特征，这可能与两种蛋白质磷酸化和与变构激活剂Ste5接合的差异能力有关。然后，我们将研究扩展到其他与进化相关的MAPK。我们表明，可以沿着其进化树追踪定义Fus3和Kss1不同调节特征的动力学和能量特征。总的来说,我们的方法能够重新连接（潜在的）变构与蛋白质结构稳定和动力学的主要元素，显示了在Ste5出现之前，MAPK结构中的变构调节是如何加密的。
