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Selectivity filter modalities and rapid inactivation of the hERG1 channel.
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2020-01-24 , DOI: 10.1073/pnas.1909196117
Williams E Miranda 1 , Kevin R DeMarco 2 , Jiqing Guo 3 , Henry J Duff 3 , Igor Vorobyov 2, 4 , Colleen E Clancy 4, 5 , Sergei Yu Noskov 6
Affiliation  

The human ether-á-go-go-related gene (hERG1) channel conducts small outward K+ currents that are critical for cardiomyocyte membrane repolarization. The gain-of-function mutation N629D at the outer mouth of the selectivity filter (SF) disrupts inactivation and K+-selective transport in hERG1, leading to arrhythmogenic phenotypes associated with long-QT syndrome. Here, we combined computational electrophysiology with Markov state model analysis to investigate how SF-level gating modalities control selective cation transport in wild-type (WT) and mutant (N629D) hERG1 variants. Starting from the recently reported cryogenic electron microscopy (cryo-EM) open-state channel structure, multiple microseconds-long molecular-dynamics (MD) trajectories were generated using different cation configurations at the filter, voltages, electrolyte concentrations, and force-field parameters. Most of the K+ permeation events observed in hERG1-WT simulations occurred at microsecond timescales, influenced by the spontaneous dehydration/rehydration dynamics at the filter. The SF region displayed conductive, constricted, occluded, and dilated states, in qualitative agreement with the well-documented flickering conductance of hERG1. In line with mutagenesis studies, these gating modalities resulted from dynamic interaction networks involving residues from the SF, outer-mouth vestibule, P-helices, and S5-P segments. We found that N629D mutation significantly stabilizes the SF in a state that is permeable to both K+ and Na+, which is reminiscent of the SF in the nonselective bacterial NaK channel. Increasing the external K+ concentration induced "WT-like" SF dynamics in N629D, in qualitative agreement with the recovery of flickering currents in experiments. Overall, our findings provide an understanding of the molecular mechanisms controlling selective transport in K+ channels with a nonconventional SF sequence.

中文翻译:

选择性过滤模式和hERG1通道的快速灭活。

人类的“走走相关基因”(hERG1)通道传导小的向外K +电流,这对于心肌细胞膜的复极化至关重要。选择性过滤器(SF)外口的功能获得突变N629D破坏了hERG1中的失活和K +选择性转运,导致与长QT综合征相关的心律失常表型。在这里,我们将计算电生理学与Markov状态模型分析相结合,以研究SF级门控方式如何控制野生型(WT)和突变型(N629D)hERG1变体中的选择性阳离子转运。从最近报道的低温电子显微镜(cryo-EM)开放状态通道结构开始,在过滤器,电压,电解质浓度,使用不同阳离子配置下,产生了多微秒长的分子动力学(MD)轨迹。和力场参数。在hERG1-WT模拟中观察到的大多数K +渗透事件都发生在微秒级的时间尺度上,这受过滤器自发脱水/复水动力学的影响。SF区显示出导电,收缩,闭塞和扩张状态,与hERG1的闪烁电导的定性一致。与诱变研究一致,这些门控方式来自动态相互作用网络,涉及SF,外口前庭,P-螺旋和S5-P段的残基。我们发现,N629D突变可将SF稳定在可渗透K +和Na +的状态,这让人联想到非选择性细菌NaK通道中的SF。增加外部K +浓度会导致N629D出现“类似WT”的SF动态,在实验中与闪烁电流的恢复在质量上吻合。总体而言,我们的发现提供了对控制具有非常规SF序列的K +通道中选择性转运的分子机制的理解。
更新日期:2020-01-26
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