‘C-type’ closed state and gating mechanisms of K2P channels revealed by conformational changes of the TREK-1 channel  

作　　者：Qiansen Zhang Jie Fu Shaoying Zhang Peipei Guo Shijie Liu Juwen Shen Jiangtao Guo Huaiyu Yang 

机构地区：[1]Shanghai Key Laboratory of Regulatory Biology,Institute of Biomedical Sciences,School of Life Sciences,East China Normal University,Shanghai 200241,China [2]Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou 310058,China

出　　处：《Journal of Molecular Cell Biology》2022年第1期47-55,共9页分子细胞生物学报（英文版）

基　　金：This work was supported in part by the Ministry of Science and Technology(2018YFA0508100 to Q.Z.and J.G.);the National Natural Science Foundation of China(31800699 to Q.Z.);the Fundamental Research Funds for the Central Universities,and the‘XingFuZhiHua’funding of ECNU(44300-19311-542500/006 to H.Y.).

摘　　要：Two-pore domain potassium (K2P) channels gate primarily within the selectivity filter, termed ‘C-type’ gating. Due to the lack of structural insights into the nonconductive (closed) state, ‘C-type’ gating mechanisms remain elusive. Here, molecular dynamics (MD) simulations on TREK-1, a K2P channel, revealed that M4 helix movements induce filter closing in a novel ‘deeper-down’ structure that represents a ‘C-type’ closed state. The ‘down’ structure does not represent the closed state as previously proposed and instead acts as an intermediate state in gating. The study identified the allosteric ‘seesaw’ mechanism of M4 helix movements in modulating filter closing. Finally, guided by this recognition of K2P gating mechanisms, MD simulations revealed that gain-of-function mutations and small-molecule activators activate TREK-1 by perturbing state transitions from open to closed states. Together, we reveal a ‘C-type’ closed state and provide mechanical insights into gating procedures and allosteric regulations for K2P channels.

关 键 词：K2P STATE selectivity filter C-type GATING 

分 类 号：O62[理学—有机化学]