Positive selection-guided mutational analysis revealing two key functional sites of scorpion ERG K(+) channel toxins.
Positive selection-guided mutational analysis revealing two key functional sites of scorpion ERG K(+) channel toxins.
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DOI：
10.1016/j.bbrc.2012.10.065
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发表时间：
2012-12
影响因子：
3.1
通讯作者：
Xuelin Wang;J. M. Jiménez-Vargas;Chenqi Xu;L. Possani;Shunyi Zhu
中科院分区：
文献类型：
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作者：
Xuelin Wang;J. M. Jiménez-Vargas;Chenqi Xu;L. Possani;Shunyi Zhu
蝎子γ-KTX毒素是研究人乙醚-GO-GO相关基因(HERG)K+通道生理和药理功能的重要分子工具。为了准确定位参与通道结合的这类毒素的功能残基，我们采用了一种结合进化信息和定点突变的组合方法。在这三个正选择位点中，有两个(Gln18和Met35)被发现与毒素的功能相关，因为它们的变化显著降低了ErgTx1(也称为CnErg1)在hERG1通道上的活性。相反，当引入突变时，第三个PSS(Ala42)没有观察到效力变化，这可能是因为它的位置远离毒素的功能表面。我们的策略将加速蝎子K+通道毒素结构-功能关系的研究。
Scorpion γ-KTx toxins are important molecular tools for studying physiological and pharmacological functions of human ether-á-go-go related gene (hERG) K+channels. To pinpoint functional residues of this class of toxins involved in channel binding, we employed a combined approach that integrates evolutionary information and site-directed mutagenesis. Among three positively selected sites (PSSs) identified here, two (Gln18 and Met35) were found to be associated with the toxin’s function because their changes significantly decreased the potency of ErgTx1 (also called CnErg1) on hERG1 channel. On the contrary, no potency alteration was observed at the third PSS (Ala42) when the mutation was introduced, which could be due to its location far from the functional surface of the toxin. Our strategy will accelerate the research of structure–function relationship of scorpion K+channel toxins.