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电压传感器之间的直接相互作用在电压门控H⁺通道二聚体中产生协同持续失活。

Direct Interaction between the Voltage Sensors Produces Cooperative Sustained Deactivation in Voltage-gated H+ Channel Dimers.

作者信息

Okuda Hiroko, Yonezawa Yasushige, Takano Yu, Okamura Yasushi, Fujiwara Yuichiro

机构信息

From Division of Integrative Physiology, Graduate School of Medicine.

the High Pressure Protein Research Center, Institute of Advanced Technology, Kinki University, Kinokawa 649-6493, Wakayama, Japan, and.

出版信息

J Biol Chem. 2016 Mar 11;291(11):5935-5947. doi: 10.1074/jbc.M115.666834. Epub 2016 Jan 11.

Abstract

The voltage-gated H(+) channel (Hv) is a voltage sensor domain-like protein consisting of four transmembrane segments (S1-S4). The native Hv structure is a homodimer, with the two channel subunits functioning cooperatively. Here we show that the two voltage sensor S4 helices within the dimer directly cooperate via a π-stacking interaction between Trp residues at the middle of each segment. Scanning mutagenesis showed that Trp situated around the original position provides the slow gating kinetics characteristic of the dimer's cooperativity. Analyses of the Trp mutation on the dimeric and monomeric channel backgrounds and analyses with tandem channel constructs suggested that the two Trp residues within the dimer are functionally coupled during Hv deactivation but are less so during activation. Molecular dynamics simulation also showed direct π-stacking of the two Trp residues. These results provide new insight into the cooperative function of voltage-gated channels, where adjacent voltage sensor helices make direct physical contact and work as a single unit according to the gating process.

摘要

电压门控H(+)通道(Hv)是一种类似电压传感器结构域的蛋白质,由四个跨膜片段(S1 - S4)组成。天然Hv结构是一个同型二聚体,两个通道亚基协同发挥作用。在此我们表明,二聚体内的两个电压传感器S4螺旋通过每个片段中间的色氨酸残基之间的π-堆积相互作用直接协同。扫描诱变表明,位于原始位置附近的色氨酸提供了二聚体协同作用的慢门控动力学特征。对二聚体和单体通道背景上的色氨酸突变分析以及串联通道构建体分析表明,二聚体内的两个色氨酸残基在Hv失活过程中功能偶联,但在激活过程中偶联程度较低。分子动力学模拟也显示了两个色氨酸残基的直接π-堆积。这些结果为电压门控通道的协同功能提供了新的见解,其中相邻的电压传感器螺旋直接进行物理接触,并根据门控过程作为一个整体发挥作用。

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