Atomistic mechanism of coupling between cytosolic sensor domain and selectivity filter in TREK K2P channels.

TitleAtomistic mechanism of coupling between cytosolic sensor domain and selectivity filter in TREK K2P channels.
Publication TypeJournal Article
Year of Publication2024
AuthorsT├╝rkaydin B, Schewe M, Riel EBarbara, Schulz F, Biedermann J, Baukrowitz T, Sun H
JournalNat Commun
Volume15
Issue1
Pagination4628
Date Published2024 May 31
ISSN2041-1723
KeywordsAnimals, Crystallography, X-Ray, Cytosol, HEK293 Cells, Humans, Ion Channel Gating, Molecular Dynamics Simulation, Phosphorylation, Potassium Channels, Tandem Pore Domain, Protein Domains
Abstract

The two-pore domain potassium (K2P) channels TREK-1 and TREK-2 link neuronal excitability to a variety of stimuli including mechanical force, lipids, temperature and phosphorylation. This regulation involves the C-terminus as a polymodal stimulus sensor and the selectivity filter (SF) as channel gate. Using crystallographic up- and down-state structures of TREK-2 as a template for full atomistic molecular dynamics (MD) simulations, we reveal that the SF in down-state undergoes inactivation via conformational changes, while the up-state structure maintains a stable and conductive SF. This suggests an atomistic mechanism for the low channel activity previously assigned to the down state, but not evident from the crystal structure. Furthermore, experimentally by using (de-)phosphorylation mimics and chemically attaching lipid tethers to the proximal C-terminus (pCt), we confirm the hypothesis that moving the pCt towards the membrane induces the up-state. Based on MD simulations, we propose two gating pathways by which movement of the pCt controls the stability (i.e., conductivity) of the filter gate. Together, these findings provide atomistic insights into the SF gating mechanism and the physiological regulation of TREK channels by phosphorylation.

DOI10.1038/s41467-024-48823-y
Alternate JournalNat Commun
PubMed ID38821927
PubMed Central IDPMC11143257
Grant ListRU2518 / / Deutsche Forschungsgemeinschaft (German Research Foundation) /
EXC 2008/1-390540038 / / Deutsche Forschungsgemeinschaft (German Research Foundation) /