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Pathological turret mutations in the cardiac sodium channel cause long-range pore disruption
bioRxiv - Biochemistry Pub Date : 2021-01-17 , DOI: 10.1101/2021.01.15.426807
Zaki F Habib , Manas Kohli , Samantha C Salvage , Taufiq Rahman , Christopher L-H Huang , Antony P Jackson

The voltage-gated sodium channel Nav1.5 initiates the cardiac action potential. Germline mutations that disrupt Nav1.5 activity predispose affected individuals to inherited cardiopathologies. Some of these Nav1.5 mutations alter amino acids in extracellular turret domains DII and DIII. Yet the mechanism is unclear. In the rat Nav1.5 structure determined by cryogenic electron microscopy, the wild-type residues corresponding to these mutants form a complex salt-bridge between the DII and DIII turret interface. Furthermore, adjacent aromatic residues form cation-π interactions with the complex salt-bridge. Here, we examine this region using site-directed mutagenesis, electrophysiology and in silico modeling. We confirm functional roles for the salt-bridges and the aromatic residues. We show that their disruption perturbs the geometry of both the DEKA selectivity ring and the inner pore vestibule that are crucial for sodium ion permeability. Our findings provide insights into a class of pathological mutations occurring not only in Nav1.5 but also in other sodium channel isoforms too. Our work illustrates how the sodium channel structures now being reported can be used to formulate and guide novel functional hypotheses.

中文翻译:

心脏钠通道中的病理性刀塔突变导致远距离毛孔破坏

电压门控钠通道Nav1.5启动心脏动作电位。破坏Nav1.5活性的生殖系突变使受影响的个体易患遗传性心脏病。这些Nav1.5突变中的一些会改变细胞外炮塔结构域DII和DIII中的氨基酸。但是机制尚不清楚。在通过低温电子显微镜确定的大鼠Nav1.5结构中,对应于这些突变体的野生型残基在DII和DIII炮塔界面之间形成了复杂的盐桥。此外,相邻的芳族残基与复合盐桥形成阳离子-π相互作用。在这里,我们使用定点诱变,电生理学和计算机模拟来检查该区域。我们确认了盐桥和芳香族残基的功能作用。我们表明,它们的破坏扰乱了DEKA选择性环和内部孔前庭的几何形状,这对于钠离子渗透性至关重要。我们的发现为一类不仅在Nav1.5中发生而且也在其他钠通道亚型中发生的病理突变提供了见识。我们的工作说明了如何将目前报道的钠通道结构用于制定和指导新颖的功能假设。
更新日期:2021-01-18
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