Scorpion Toxins: Positive Selection at a Distal Site Modulates Functional Evolution at a Bioactive Site
Scorpion Toxins: Positive Selection at a Distal Site Modulates Functional Evolution at a Bioactive Site
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蝎子毒素：远端位点的正选择调节生物活性位点的功能进化
DOI：
10.1093/molbev/msy223
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发表时间：
2018-12
影响因子：
10.7
通讯作者：
Zhu Shunyi
中科院分区：
文献类型：
--
作者：
Zhu Limei;Gao Bin;Shouli Yuan;Zhu Shunyi
摘要蛋白质的生物活性位点是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，它们经常经历积极的选择，以应对来自竞争对手的目标变化。然而，一些远离蛋白质及其靶标界面的位点也被确定为在正选择下进化。在这里，我们采用实验和计算相结合的方法探讨了这种位点在蝎子α型毒素影响钠（Na+）通道（简称α-ScNaTxs）中的进化意义。我们发现，尽管没有直接参与与Na+通道的相互作用，但不同类型氨基酸在该位点的突变导致三种α-ScNaTxs对大鼠和昆虫的毒性变化，并伴随对其结构的不同影响。分子动力学模拟表明，突变通过变构通信改变了阳性选择的含有生物活性位点的功能区的构象动力学，表明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非生物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，以保持通道结合的活性构象。这可能有助于合理设计蝎子Na+通道毒素，并通过修饰远端非生物活性位点来提高系统选择性。
Abstract 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.
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DOI：
10.1007/978-3-319-77525-8_100075
发表时间：
2018-12
期刊：
Encyclopedia of Big Data Technologies
影响因子：
--
作者：
通讯作者：
--
影响因子：
3
作者：
通讯作者：
--
DOI：
10.1210/jcem.85.1.6229
发表时间：
2000
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1109/icmas.2000.858517
发表时间：
2000-07
期刊：
Proceedings Fourth International Conference on MultiAgent Systems
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.4
作者：
Jones OD;Schall JD;Shen FX
通讯作者：
Shen FX