Structural Basis of Lipid-Driven Conformational Transitions in the KvAP Voltage Sensing Domain

Voltage-gated ion channels respond to transmembrane electric fields through reorientations of the positively charged S4 helix within the voltage-sensing domain (VSD). Despite a wealth of structural and functional data, the details of this conformational change remain controversial. Recent electrophysiological evidence showed that equilibrium between the resting (Down) and activated (Up) conformations of KvAP-VSD from Aeropyrum pernix can be biased through reconstitution in lipids with or without phosphate groups. We investigated the structural transition between these functional states using site-directed spin labeling and EPR spectroscopic methods. Solvent accessibility and inter-helical distance determinations suggest that KvAP gates through S4 movements involving a ~3 Å upward tilt and simultaneous ~2 Å axial shift. This motion leads to large accessibly changes in the intracellular water-filled crevice and supports a novel model of gating that combines structural rearrangements and electric field remodeling.