Transition between conformational states of the TREK-1 K2P channel promoted by interaction with PIP2

Journal article

Members of the TREK family of two-pore domain potassium channels are highly sensitive to regulation by membrane lipids, including phosphatidylinositol-4,5-bisphosphate (PIP₂). Previous studies have demonstrated that PIP₂ increases TREK-1 channel activity; however, the mechanistic understanding of the conformational transitions induced by PIP₂ remain unclear. Here, we used coarse-grained molecular dynamics and atomistic molecular dynamics simulations to model the PIP₂-binding site on both the up and down state conformations of TREK-1. We also calculated the free energy of PIP₂ binding relative to other anionic phospholipids in both conformational states using potential of mean force and free-energy-perturbation calculations. Our results identify state-dependent binding of PIP₂ to sites involving the proximal C-terminus, and we show that PIP₂ promotes a conformational transition from a down state toward an intermediate that resembles the up state. These results are consistent with functional data for PIP₂ regulation, and together provide evidence for a structural mechanism of TREK-1 channel activation by phosphoinositides.

Authors: Panasawatwong, A; Pipatpolkai, T; Tucker, SJ

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Biophysical Journal
• Volume: 121
• Issue: 12
• Pages: 2380-2388
• Publication date: 2022-06-21
• Acceptance date: 2022-05-16
• DOI: 10.1016/j.bpj.2022.05.019
• EISSN: 1542-0086
• ISSN: 0006-3495
• Pmid: 35596528
• Language: English
• Keywords: molecular dynamics simulation; molecular conformation; potassium channels, tandem pore domain; binding sites; FFR; phosphatidylinositol 4,5-diphosphate