Evidence for domain-specific recognition of SK and Kv channels by MTX and HsTx1 scorpion toxins
Evidence for domain-specific recognition of SK and Kv channels by MTX and HsTx1 scorpion toxins
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DOI：
10.1074/jbc.m410055200
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发表时间：
2004-12-31
影响因子：
4.8
通讯作者：
Sabatier, JM
中科院分区：
文献类型：
--
作者：
Regaya, I;Beeton, C;Sabatier, JM
Maurotoxin （MTX）和HsTx1是蝎子α - ktx6结构家族的两种毒素。这34个残基毒素由4个二硫桥交联，具有59%的序列同一性，并沿着经典的α / β支架折叠。尽管有这些结构上的相似之处，它们在药理方面却完全不同。MTX在小（SK）和中（IK）电导Ca2+激活（K+）通道和电压门控Kv1.2通道上高度活跃，而HsTx1仅能阻断电压门控Kv1.1和Kv1.3通道。在这里，我们设计并化学生产了MTX-HsTx1，这是两种毒素的嵌合体，包含MTX的n端螺旋区（序列1-16）和HsTx1的c端β -sheet区（序列17-34）。用H-1 NMR对溶液中肽的三维结构进行了解析。MTX-HsTx1显示了MTX在SK通道上的活性，而HsTx1在Kv1.1、Kv1.2、Kv1.3和IK通道上的药理特征。这些数据表明，MTX的螺旋区域在SK通道识别中发挥关键作用，而HsTx1的β -sheet区域对所有其他通道类型的活性至关重要。
Maurotoxin (MTX) and HsTx1 are two scorpion toxins belonging to the alpha-KTx6 structural family. These 34-residue toxins, cross-linked by four disulfide bridges, share 59% sequence identity and fold along the classical alpha/beta scaffold. Despite these structural similarities, they fully differ in their pharmacological profiles. MTX is highly active on small (SK) and intermediate (IK) conductance Ca2+-activated (K+) channels and on voltage-gated Kv1.2 channel, whereas HsTx1 potently blocks voltage-gated Kv1.1 and Kv1.3 channels only. Here, we designed and chemically produced MTX-HsTx1, a chimera of both toxins that contains the N-terminal helical region of MTX (sequence 1-16) and the C-terminal beta-sheet region of HsTx1 (sequence 17-34). The three-dimensional structure of the peptide in solution was solved by H-1 NMR. MTX-HsTx1 displays the activity of MTX on SK channel, whereas it exhibits the pharmacological profile of HsTx1 on Kv1.1, Kv1.2, Kv1.3, and IK channels. These data demonstrate that the helical region of MTX exerts a key role in SK channel recognition, whereas the beta-sheet region of HsTx1 is crucial for activity on all other channel types tested.