Comparative structural analysis of human Nav1.1 and Nav1.5 reveals mutational hotspots for sodium channelopathies
Comparative structural analysis of human Nav1.1 and Nav1.5 reveals mutational hotspots for sodium channelopathies
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DOI：
10.1073/pnas.2100066118
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发表时间：
2021-03-16
影响因子：
11.1
通讯作者：
Yan, Nieng
中科院分区：
文献类型：
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作者：
Pan, Xiaojing;Li, Zhangqiang;Yan, Nieng
在人类电压门控钠（Na-v）通道的九种亚型中，脑和心脏亚型Na（v）1.1和Na（v）1.5各自携带分别与癫痫和心脏疾病相关的400多个错义突变。高分辨率结构是疾病变异体的结构-功能关系解剖所必需的。我们报告了全长人Na（v）1.1-β 4复合物的3.3 A分辨率的冷冻电镜结构，并在随附的论文中报告了Na（v）1.5-E1784 K变体。分别解决了Na（v）1.1和Na（v）1.5中高达341和261个疾病相关错义突变。比较结构分析揭示了Na（v）1.1和Na（v）1.5共同的几个疾病突变簇。其中，大多数突变的细胞外环以上的孔域和支持段的选择性过滤器可能会损害结构的完整性，而那些孔域和电压敏感域主要干扰机电耦合和快速失活。我们对这些突变的系统性结构描述为其致病机制提供了重要的见解，这将有助于开发针对各种钠通道病的精确治疗干预措施。
Among the nine subtypes of human voltage-gated sodium (Na-v) channels, the brain and cardiac isoforms, Na(v)1.1 and Na(v)1.5, each carry more than 400 missense mutations respectively associated with epilepsy and cardiac disorders. High-resolution structures are required for structure-function relationship dissection of the disease variants. We report the cryo-EM structures of the full-length human Na(v)1.1-beta 4 complex at 3.3 A resolution here and the Na(v)1.5-E1784K variant in the accompanying paper. Up to 341 and 261 disease-related missense mutations in Na(v)1.1 and Na(v)1.5, respectively, are resolved. Comparative structural analysis reveals several clusters of disease mutations that are common to both Na(v)1.1 and Na(v)1.5. Among these, the majority of mutations on the extracellular loops above the pore domain and the supporting segments for the selectivity filter may impair structural integrity, while those on the pore domain and the voltage-sensing domains mostly interfere with electromechanical coupling and fast inactivation. Our systematic structural delineation of these mutations provides important insight into their pathogenic mechanism, which will facilitate the development of precise therapeutic interventions against various sodium channelopathies.