Conformational Switch between Slow and Fast Gating Modes Allosteric Regulation of Voltage Sensor Mobility in the EAG K+ Channel

Voltage-gated EAG K+ channels switch between fast and slow gating modes in a Mg2+-dependent manner by an unknown mechanism. We analyzed molecular motions in and around the voltage-sensing S4 in bEAG1. Using accessibility and perturbation analyses, we found that activation increases both the charge occupancy and volume of S4 side chains in the gating canal. Fluorescence measurements suggest that mode switching is due to a motion of the S2/S3 side of the gating canal. We propose that when S4 is in the resting state and its thin end is in the gating canal, a conformational rearrangement of S2/S3 narrows the canal around S4, forming the Mg2+ binding site. Binding of Mg2+ is proposed to stabilize this conformation and to slow opening of the gate by impeding S4's voltage-sensing outward motion.