Analysis of residue–residue interactions in the structures of ASIC1a suggests possible gating mechanisms

The gating mechanism of acid-sensitive ion channels (ASICs) remains unclear, despite the availability of atomic-scale structures in various functional states. The collapse of the acidic pocket and structural changes in the low-palm region are assumed to trigger activation. For the acidic pocket, protonation of some residues can minimize repulsion in the collapsed conformation. The relationship between low-palm rearrangements and gating is unknown. In this work, we performed a Monte Carlo energy optimization of known ASIC1a structures and determined the residue–residue interactions in different functional states. For rearrangements in the acidic pocket, our results are consistent with previously proposed mechanisms, although significant complexity was revealed for the residue–residue interactions. The data support the proposal of a gating mechanism in the low-palm region, in which residues E80 and E417 share a proton to activate the channel.