A general mechanism of KCNE1 modulation of KCNQ1 channels involving non-canonical VSD-PD coupling.
A general mechanism of KCNE1 modulation of KCNQ1 channels involving non-canonical VSD-PD coupling.
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DOI：
10.1038/s42003-021-02418-1
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发表时间：
2021-07-20
影响因子：
5.9
通讯作者：
Larsson HP
中科院分区：
文献类型：
--
作者：
Wu X;Perez ME;Noskov SY;Larsson HP
电压门控KCNQ 1通道包含四个独立的电压敏感结构域（VSD）和一个孔结构域（PD）。当VSD处于中间状态时，单独表达的KCNQ 1打开。在心肌细胞中，与KCNE 1共表达的KCNQ 1主要在VSD处于完全激活状态时打开。KCNE 1还大大减缓了KCNQ 1通道的开放，并使开放的电压依赖性偏移>40 mV。我们在这里表明，在VSD-PD接口的保守残基的突变改变VSD-PD耦合，使突变KCNQ 1/KCNE 1通道打开中间VSD状态。利用KCNQ 1和KCNE β亚基在不同状态下的最新结构，我们提出了一种机制，通过该机制，KCNE 1使VSD相对于PD旋转，并以非经典方式影响KCNQ 1通道的VSD-PD耦合，迫使KCNQ 1/KCNE 1通道在完全激活的VSD状态下打开。这可以解释KCNE 1对KCNQ 1通道的许多诱导作用。Wu等证明KCNE 1通过KCNE 1诱导的旋转调节电压敏感结构域和孔结构域之间的偶联，从而对钾通道KCNQ 1功能发挥作用。作为这种旋转的结果，发生残留物碰撞，其禁止电压传感器的导电中间状态构造的形成。
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. Wu et al. demonstrate that KCNE1 exerts its effects on potassium channel KCNQ1 function by regulating the coupling between the voltage-sensing domain and pore domain via KCNE1-induced rotation. As a consequence of this rotation, residue clashes occur that prohibit the formation of a conductive intermediate state conformation of the voltage sensor.
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影响因子：
3.3
作者：
Klauda, Jeffery B.;Venable, Richard M.;Freites, J. Alfredo;O'Connor, Joseph W.;Tobias, Douglas J.;Mondragon-Ramirez, Carlos;Vorobyov, Igor;MacKerell, Alexander D., Jr.;Pastor, Richard W.
通讯作者：
Pastor, Richard W.
影响因子：
44.1
作者：
Li, Xiaoxiao;Zhang, Qiansen;Guo, Jiangtao
通讯作者：
Guo, Jiangtao
影响因子：
5.5
作者：
Best, Robert B.;Zhu, Xiao;Shim, Jihyun;Lopes, Pedro E. M.;Mittal, Jeetain;Feig, Michael;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.
影响因子：
16.6
作者：
Hou P;Eldstrom J;Shi J;Zhong L;McFarland K;Gao Y;Fedida D;Cui J
通讯作者：
Cui J
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML