Structural mechanisms for the activation of human cardiac KCNQ1 channel by electro-mechanical coupling enhancers

作者：Demin Ma, Ling Zhong, Zhenzhen Yan, Jing Yao, Yan Zhang, Fan Ye, Yuan Huang, Dongwu Lai, Wei Yang, Panpan Hou, Jiangtao Guo · 发表于：Proceedings of the National Academy of Sciences · 年份：2022 · DOI：10.1073/pnas.2207067119 · 被引用次数：57 · 研究领域：Cardiac electrophysiology and arrhythmias、Ion channel regulation and function、Force Microscopy Techniques and Applications

The cardiac KCNQ1 potassium channel carries the important I Ks current and controls the heart rhythm. Hundreds of mutations in KCNQ1 can cause life-threatening cardiac arrhythmia. Although KCNQ1 structures have been recently resolved, the structural basis for the dynamic electro-mechanical coupling, also known as the voltage sensor domain–pore domain (VSD-PD) coupling, remains largely unknown. In this study, utilizing two VSD-PD coupling enhancers, namely, the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP 2 ) and a small-molecule ML277, we determined 2.5–3.5 Å resolution cryo-electron microscopy structures of full-length human KCNQ1-calmodulin (CaM) complex in the apo closed, ML277-bound open, and ML277-PIP 2 -bound open states. ML277 binds at the “elbow” pocket above the S4-S5 linker and directly induces an upward movement of the S4-S5 linker and the opening of the activation gate without affecting the C-terminal domain (CTD) of KCNQ1. PIP 2 binds at the cleft between the VSD and the PD and brings a large structural rearrangement of the CTD together with the CaM to activate the PD. These findings not only elucidate the structural basis for the dynamic VSD-PD coupling process during KCNQ1 gating but also pave the way to develop new therapeutics for anti-arrhythmia.