Group of Peptide Biology and Evolution, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China.
Mol Biol Evol. 2019 Feb 1;36(2):365-375. doi: 10.1093/molbev/msy223.
The bioactive sites of proteins are those that directly interact with their targets. In many immunity- and predation-related proteins, they frequently experience positive selection for dealing with the changes of their targets from competitors. However, some sites that are far away from the interface between proteins and their targets are also identified to evolve under positive selection. Here, we explore the evolutionary implication of such a site in scorpion α-type toxins affecting sodium (Na+) channels (abbreviated as α-ScNaTxs) using a combination of experimental and computational approaches. We found that despite no direct involvement in interaction with Na+ channels, mutations at this site by different types of amino acids led to toxicity change on both rats and insects in three α-ScNaTxs, accompanying differential effects on their structures. Molecular dynamics simulations indicated that the mutations changed the conformational dynamics of the positively selected bioactive site-containing functional regions by allosteric communication, suggesting a potential evolutionary correlation between these bioactive sites and the distant nonbioactive site. Our results reveal for the first time the cause of fast evolution at nonbioactive sites of scorpion neurotoxins, which is presumably to adapt to the change of their bioactive sites through coevolution to maintain an active conformation for channel binding. This might aid rational design of scorpion Na+ channel toxins with improved phyletic selectivity via modification of a distant nonbioactive site.
蛋白质的生物活性位点是那些直接与其靶标相互作用的位点。在许多与免疫和捕食相关的蛋白质中，它们经常经历正选择，以应对其靶标从竞争中发生的变化。然而，一些远离蛋白质与其靶标之间界面的位点也被确定为在正选择下进化。在这里，我们使用实验和计算相结合的方法，探讨了这种位于影响钠离子（Na+）通道的蝎子 α 型毒素（简称 α-ScNaTxs）中的位点的进化意义。我们发现，尽管该位点不直接参与与 Na+通道的相互作用，但在三种 α-ScNaTxs 中，不同类型的氨基酸在该位点的突变导致对大鼠和昆虫的毒性发生变化，同时对其结构产生不同的影响。分子动力学模拟表明，这些突变通过变构通讯改变了包含生物活性位点的功能区域的构象动力学，提示这些生物活性位点与远处的非生物活性位点之间存在潜在的进化相关性。我们的研究结果首次揭示了蝎子神经毒素中非活性位点快速进化的原因，这可能是通过共同进化来适应其生物活性位点的变化，以维持对通道结合的活性构象。这可能有助于通过修饰远处的非生物活性位点，设计具有改进的种系选择性的蝎子 Na+通道毒素。
