N-type fast inactivation of a eukaryotic voltage-gated sodium channel.
N-type fast inactivation of a eukaryotic voltage-gated sodium channel.
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DOI：
10.1038/s41467-022-30400-w
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发表时间：
2022-05-17
影响因子：
16.6
通讯作者：
Jiang, Daohua
中科院分区：
文献类型：
--
作者：
Zhang, Jiangtao;Shi, Yiqiang;Fan, Junping;Chen, Huiwen;Xia, Zhanyi;Huang, Bo;Jiang, Juquan;Gong, Jianke;Huang, Zhuo;Jiang, Daohua
电压门控钠（NaV）通道启动动作电位。由Ile-Phe-Met基序介导的NaV通道的快速失活对于防止过度兴奋和调节放电频率至关重要。在这里，我们提出的cryo-electron显微镜结构的NaVEh从球石藻Emiliania huxleyi，这揭示了一个意想不到的分子门控机制NaV通道快速失活独立的Ile-Phe-Met基序。NaVEh的N-末端螺旋插入开放的激活门并阻断它。螺旋的结合姿势通过多重静电相互作用稳定。删除螺旋或突变阻断静电相互作用完全取消了快速失活。这些强相互作用使得快速失活成为可能，但也延迟了从快速失活中恢复，这比人类NaV通道慢约160倍。总之，我们的研究结果提供了NaVEh快速失活的机制见解，从根本上不同于传统的局部变构抑制，揭示了令人惊讶的结构多样性和离子通道失活的功能保护。电压门控钠通道介导电信号。在这里，作者报告了来自海洋植物Emiliania huxleyi的NaVEh的冷冻电镜结构，揭示了一种意想不到的N型快速失活机制。
Voltage-gated sodium (NaV) channels initiate action potentials. Fast inactivation of NaV channels, mediated by an Ile-Phe-Met motif, is crucial for preventing hyperexcitability and regulating firing frequency. Here we present cryo-electron microscopy structure of NaVEh from the coccolithophore Emiliania huxleyi, which reveals an unexpected molecular gating mechanism for NaV channel fast inactivation independent of the Ile-Phe-Met motif. An N-terminal helix of NaVEh plugs into the open activation gate and blocks it. The binding pose of the helix is stabilized by multiple electrostatic interactions. Deletion of the helix or mutations blocking the electrostatic interactions completely abolished the fast inactivation. These strong interactions enable rapid inactivation, but also delay recovery from fast inactivation, which is ~160-fold slower than human NaV channels. Together, our results provide mechanistic insights into fast inactivation of NaVEh that fundamentally differs from the conventional local allosteric inhibition, revealing both surprising structural diversity and functional conservation of ion channel inactivation. Voltage-gated sodium channels mediate electrical signaling. Here, authors report the cryo-EM structure of NaVEh from the marine plant Emiliania huxleyi, revealing an unexpected mechanism of N-type fast inactivation.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.4
作者：
Favre, I;Moczydlowski, E;Schild, L
通讯作者：
Schild, L
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
56.9
作者：
HOSHI, T;ZAGOTTA, WN;ALDRICH, RW
通讯作者：
ALDRICH, RW
影响因子：
14.8
作者：
通讯作者：
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