Groome James R, Bayless-Edwards Landon
Department of Biological Sciences, Idaho State University, Pocatello, ID, United States.
Oregon Health and Sciences University School of Medicine, Portland, OR, United States.
Front Pharmacol. 2020 Feb 28;11:160. doi: 10.3389/fphar.2020.00160. eCollection 2020.
Voltage-gated ion channels share a common structure typified by peripheral, voltage sensor domains. Their S4 segments respond to alteration in membrane potential with translocation coupled to ion permeation through a central pore domain. The mechanisms of gating in these channels have been intensely studied using pioneering methods such as measurement of charge displacement across a membrane, sequencing of genes coding for voltage-gated ion channels, and the development of all-atom molecular dynamics simulations using structural information from prokaryotic and eukaryotic channel proteins. One aspect of this work has been the description of the role of conserved negative countercharges in S1, S2, and S3 transmembrane segments to promote sequential salt-bridge formation with positively charged residues in S4 segments. These interactions facilitate S4 translocation through the lipid bilayer. In this review, we describe functional and computational work investigating the role of these countercharges in S4 translocation, voltage sensor domain hydration, and in diseases resulting from countercharge mutations.
电压门控离子通道具有共同的结构，其典型特征是外周电压传感器结构域。它们的S4片段通过与通过中央孔结构域的离子渗透偶联的易位来响应膜电位的变化。使用开创性方法对这些通道的门控机制进行了深入研究，例如测量跨膜电荷位移、对编码电压门控离子通道的基因进行测序，以及利用来自原核和真核通道蛋白的结构信息开展全原子分子动力学模拟。这项工作的一个方面是描述S1、S2和S3跨膜片段中保守负电荷的作用，以促进与S4片段中带正电荷的残基形成连续盐桥。这些相互作用有助于S4通过脂质双层易位。在本综述中，我们描述了功能和计算工作，这些工作研究了这些负电荷在S4易位、电压传感器结构域水化以及由负电荷突变导致的疾病中的作用。
