Key result
PIP2 binds to the proximal C-terminus of TREK-1 with higher affinity in the up state (-41 kJ/mol) compared to the down state (-26 kJ/mol) and promotes a conformational transition towards the up state.
Why the study?
Members of the TREK family of two-pore domain potassium channels are highly sensitive to regulation by membrane lipids, including PIP2, but the structural mechanism remained to be modeled.
Effect estimate: -41 ± 3 kJ mol-1 (up state) vs -26 ± 2 kJ mol-1 (down state)
This computational study provides evidence for a structural mechanism of TREK-1 channel activation by phosphoinositides via state-dependent PIP2 binding.
Hypothesis-generating for TREK-1 modulation; leaves open translation to cardiac electrophysiology in vivo.
Members of the TREK family of two-pore domain (K2P) potassium channels are highly sensitive to regulation by membrane lipids, including phosphatidylinositol-4,5-bisphosphate (PIP 2 ). This study used coarse-grained molecular dynamics (CG-MD) and atomistic MD simulations to model the PIP 2 binding site on both the up and down state conformations of TREK-1. We also calculated the free energy of PIP 2 binding relative to other anionic phospholipids in both conformational states using potential of mean force (PMF) and free energy perturbation (FEP) calculations. Our results identify state-dependent binding of PIP 2 to sites involving the proximal C-terminus and we show that PIP 2 promotes a conformational transition from a down state towards an intermediate that resembles the up state. These results are consistent with functional data for PIP 2 regulation and together provide evidence for a structural mechanism of TREK-1 channel activation by phosphoinositides.
No takes yet. Share an insight, caveat, or question.
Panasawatwong et al. (2022) studied TREK-1 K2P channel regulation. Phosphatidylinositol-4,5-bisphosphate (PIP2) vs. Apo state / other phospholipids was evaluated on Binding free energy (PMF) (-41 ± 3 kJ mol-1 (up state) vs -26 ± 2 kJ mol-1 (down state)). PIP2 binds to the proximal C-terminus of TREK-1 with higher affinity in the up state (-41 kJ/mol) compared to the down state (-26 kJ/mol) and promotes a conformational transition towards the up state.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: