一种涉及非典型 VSD-PD 偶联的 KCNE1 调节 KCNQ1 通道的通用机制。

A general mechanism of KCNE1 modulation of KCNQ1 channels involving non-canonical VSD-PD coupling.

机构信息

Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL, USA.

Centre for Molecular Simulation, Department of Biological Sciences, University of Calgary, Calgary, AB, Canada.

出版信息

Commun Biol. 2021 Jul 20;4(1):887. doi: 10.1038/s42003-021-02418-1.

DOI:10.1038/s42003-021-02418-1

PMID:34285340

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8292421/

Abstract

Voltage-gated KCNQ1 channels contain four separate voltage-sensing domains (VSDs) and a pore domain (PD). KCNQ1 expressed alone opens when the VSDs are in an intermediate state. In cardiomyocytes, KCNQ1 co-expressed with KCNE1 opens mainly when the VSDs are in a fully activated state. KCNE1 also drastically slows the opening of KCNQ1 channels and shifts the voltage dependence of opening by >40 mV. We here show that mutations of conserved residues at the VSD-PD interface alter the VSD-PD coupling so that the mutant KCNQ1/KCNE1 channels open in the intermediate VSD state. Using recent structures of KCNQ1 and KCNE beta subunits in different states, we present a mechanism by which KCNE1 rotates the VSD relative to the PD and affects the VSD-PD coupling of KCNQ1 channels in a non-canonical way, forcing KCNQ1/KCNE1 channels to open in the fully-activated VSD state. This would explain many of the KCNE1-induced effects on KCNQ1 channels.

摘要

电压门控 KCNQ1 通道包含四个独立的电压感应域（VSD）和一个孔域（PD）。KCNQ1 单独表达时，当 VSD 处于中间状态时会打开。在心肌细胞中，KCNQ1 与 KCNE1 共同表达时，主要在 VSD 完全激活时打开。KCNE1 还大大减慢了 KCNQ1 通道的打开速度，并使打开的电压依赖性改变超过 40 mV。我们在这里表明，VSD-PD 界面保守残基的突变改变了 VSD-PD 偶联，从而使突变的 KCNQ1/KCNE1 通道在中间 VSD 状态下打开。利用最近 KCNQ1 和 KCNEβ亚基在不同状态下的结构，我们提出了一种机制，即 KCNE1 相对于 PD 旋转 VSD，并以非经典的方式影响 KCNQ1 通道的 VSD-PD 偶联，迫使 KCNQ1/KCNE1 通道在完全激活的 VSD 状态下打开。这将解释 KCNE1 对 KCNQ1 通道的许多影响。