Sodium Ion Coordination in the Selectivity Filter of a Voltage-Gated Sodium Channel
Sodium Ion Coordination in the Selectivity Filter of a Voltage-Gated Sodium Channel
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电压门控钠通道选择性过滤器中的钠离子配位
DOI：
10.1016/j.bpj.2014.11.2681
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发表时间：
2015
影响因子：
3.4
通讯作者：
Naylor C
中科院分区：
文献类型：
--
作者：
Naylor C
电压门控钠通道对于跨真核细胞膜的电信号传递是必不可少的。它们对钠离子的选择性强于其他阳离子，因此能够实现与动作电位相关的事件的微调级联。来自海洋磁球菌的原核钠通道孔NavMs的新的高分辨率晶体结构提供了钠离子在钠通道的选择性过滤器内的位置的第一个视图。结构显示三个钠离子结合在选择性过滤器内。与钾通道中的钾离子不同，这些通道中的钠离子似乎是水合的，并且不与多肽骨架直接接触，而是与保守的主链谷氨酸和丝氨酸残基以及骨架羰基原子相互作用，所有这些都可能由无序的水合壳介导。对结构的静电计算与Na+、Li+>> K+、Ca+的相对阳离子选择性相容，其对应于对这些通道测量的离子渗透率比。保守的谷氨酸178突变为天冬氨酸导致通过孔的钠离子电导降低。有趣的是，我们的E178D突变体的结构表明，它缺乏最接近细胞外前庭和最密切相关的天然结构中的E178的钠离子，解释了降低的电导。这些结果提供了对钠选择性的生物物理决定因素的深入了解，钠选择性启动其他离子通道的开放以形成动作电位波形。
Voltage-gated sodium channels are essential for electrical signalling across eukaryotic cell membranes. They exhibit strong selectivity for sodium over other cations, thus enabling the finely-tuned cascade of events associated with action potentials. A new high resolution crystal structure of the prokaryotic sodium channel pore NavMs from Magnetococcus marinus provides the first view of the locations of sodium ions within the selectivity filter of a sodium channel. The structure reveals three sodium ions are bound within the selectivity filter. Unlike potassium ions in potassium channels, the sodium ions in these channels appear to be hydrated and make no direct contact with the polypeptide backbone, instead there are interactions with conserved mainchain glutamate and serine residues, as well as backbone carbonyl atoms, all of which are likely mediated by a disordered hydration shell. Electrostatic calculations on the structure are compatible with relative cation selectivities of Na+≈ Li+>> K+, Ca+, which correspond with the ion permeability ratios measured for these channels. Mutation of the conserved glutamate 178 to aspartate results in reduced sodium ion conductance through the pore. Interestingly, our structure of the E178D mutant reveals that it lacks the sodium ion nearest the extracellular vestibule and most closely associated with E178 in the native structure, explaining the reduced conductance. These results provide insight into the biophysical determinants of sodium-selectivity, which initiates the opening of other ion channels to shape the action potential waveform.