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‘C-type’ closed state and gating mechanisms of K2P channels revealed by conformational changes of the TREK-1 channel
Qiansen Zhang1,† , Jie Fu1,† , Shaoying Zhang1 , Peipei Guo1 , Shijie Liu1 , Juwen Shen1 , Jiangtao Guo2 , Huaiyu Yang1,*
1Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
2Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
These authors contributed equally to this work.
*Correspondence to:Huaiyu Yang ,
J Mol Cell Biol, Volume 14, Issue 1, January 2022, mjac002,
Keyword: K2P, state, selectivity filter, C-type, gating

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.