Structural and Functional Diversity of Acidic Scorpion Potassium Channel Toxins
Structural and Functional Diversity of Acidic Scorpion Potassium Channel Toxins
复制标题
酸性蝎钾通道毒素的结构和功能多样性
DOI：
10.1371/journal.pone.0035154
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发表时间：
2012-04-12
期刊：
影响因子：
3.7
通讯作者：
Wu, Ying-Liang
中科院分区：
文献类型：
--
作者：
Chen, Zong-Yun;Zeng, Dan-Yun;Wu, Ying-Liang
背景虽然碱性蝎子K+通道毒素(KTXS)是众所周知的药理工具和潜在的候选药物，但表征酸性KTXS对不同K+通道亚型的潜在选择性仍然具有重要意义。不幸的是，对酸性KTXS的研究多年来一直被忽视，进展缓慢。主要发现在这里，我们描述了九个新的酸性KTXS通过克隆和生物信息学分析来鉴定。其中7个属于三个新的α-KTx亚家族(α-KTx28、α-KTx29和α-KTx30)，两个是已知的κ-KTx2亚家族的新成员。ImKTx104含有三个二硫键，是α-KTx28亚家族的第一个成员，与其他已知的KTXS具有较低的序列同源性，其核磁共振结构表明ImKTx104采用了一个修饰的半胱氨酸稳定的α-螺旋-环-β-片断(CS-α/β)折叠基序，没有明显的α-螺旋和β-片断，但仍然由三个二硫键稳定。这些新发现的酸性KTXS在钾通道上表现出不同的药理作用。酸性蝎子毒素ImKTx104是第一个被发现影响KCNQ1通道的多肽抑制剂，KCNQ1通道对碱性KTXS不敏感，与人类心脏异常密切相关。ImKTx104选择性地抑制KCNQ1通道，其Kd值为11.69µM，但对碱性KTXS敏感性钾通道的抑制作用较弱。除了ImKTx104毒素外，含有半胱氨酸稳定的α-螺旋-环-螺旋(CS-α/α)折叠支架基序的HeTx204肽可以阻断Kv1.3和KCNQ1通道。StKTx23毒素具有半胱氨酸稳定的α-Helix-Loop-β-Sheet(CS-α/β)折叠基序，可以抑制Kv1.3通道，但不能抑制KCNQ1通道。结论/意义这些发现表征了酸性KTXS的结构和功能的多样性，可能会加速酸性KTXS作为药理工具和潜在药物的开发和临床应用。
Background Although the basic scorpion K+ channel toxins (KTxs) are well-known pharmacological tools and potential drug candidates, characterization the acidic KTxs still has the great significance for their potential selectivity towards different K+ channel subtypes. Unfortunately, research on the acidic KTxs has been ignored for several years and progressed slowly. Principal Findings Here, we describe the identification of nine new acidic KTxs by cDNA cloning and bioinformatic analyses. Seven of these toxins belong to three new α-KTx subfamilies (α-KTx28, α-KTx29, and α-KTx30), and two are new members of the known κ-KTx2 subfamily. ImKTx104 containing three disulfide bridges, the first member of the α-KTx28 subfamily, has a low sequence homology with other known KTxs, and its NMR structure suggests ImKTx104 adopts a modified cystine-stabilized α-helix-loop-β-sheet (CS-α/β) fold motif that has no apparent α-helixs and β-sheets, but still stabilized by three disulfide bridges. These newly described acidic KTxs exhibit differential pharmacological effects on potassium channels. Acidic scorpion toxin ImKTx104 was the first peptide inhibitor found to affect KCNQ1 channel, which is insensitive to the basic KTxs and is strongly associated with human cardiac abnormalities. ImKTx104 selectively inhibited KCNQ1 channel with a Kd of 11.69 µM, but was less effective against the basic KTxs-sensitive potassium channels. In addition to the ImKTx104 toxin, HeTx204 peptide, containing a cystine-stabilized α-helix-loop-helix (CS-α/α) fold scaffold motif, blocked both Kv1.3 and KCNQ1 channels. StKTx23 toxin, with a cystine-stabilized α-helix-loop-β-sheet (CS-α/β) fold motif, could inhibit Kv1.3 channel, but not the KCNQ1 channel. Conclusions/Significance These findings characterize the structural and functional diversity of acidic KTxs, and could accelerate the development and clinical use of acidic KTxs as pharmacological tools and potential drugs.