Figure 8.

A simple domain level model of coupling of VSD mode shifting to the gate during hERG activation/deactivation. (i) In the closed state, the N-terminal tail does not directly interact with the gate. (ii) Upon depolarization, the VSD moves in the membrane into the activated state. This upward motion is coupled to opening of the gate via direct interactions of the S4–S5 and the S6 helix. (iii) With sustained depolarization, the VSD relaxes. Relaxation of the VSD is accompanied by a conformational change of the S4–S5 linker that causes it to dissociate from its binding site on the S6. The N-terminal tail then acts as an adaptor between the S4–S5 and S6 to couple VSD return during repolarization to closing of the gate.