Physical mechanism for gating and mechano sensitivity of the human TRAAK K+ channel

Activation of mechanosensitive ion channels by physical force underlies many physiological processes including the sensation of touch, hearing and pain(1-5). TRAAK (also known as KCNK4) ion channels are neuronally expressed members of the two-pore domain K+ (K2P) channel family and are mechano sensitive'. They are involved in controlling mechanical and temperature nociception in mice'. Mechanosensitivity of TRAAK is mediated directly through the lipid bilayer it is a membrane-tension-gated channel'. However, the molecular mechanism of TRAAK channel gating and mechanosensitivity is unknown. Here we present crystal structures of TRAAK in conductive and non-conductive conformations defined by the presence of permeant ions along the conduction pathway. In the non-conductive state, a lipid acyl chain accesses the channel cavity through a 5 Awide lateral opening in the membrane inner leaflet and physically blocks ion passage. In the conductive state, rotation of a transmembrane helix (TM4) about a central hinge seals the intramembrane opening, preventing lipid block of the cavity and permitting ion entry. Additional rotation of a membrane interacting TM2-TM 3 segment, unique to mechanosensitive K2Ps, against TM4 may further stabilize the conductive conformation. Comparison of the structures reveals a biophysical explanation for TRAAK mechanosensitivity an expansion in cross-sectional area up to 2.7 nm(2) in the conductive state is expected to create a membrane-tension-dependent energy difference between conformations that promotes force activation. Our results show how tension of the lipid bilayer can be harnessed to control gating and mechanosensitivity of a eukaryotic ion channel.