Structural basis of two-stage voltage-dependent activation in K+ channels

The structure of the voltage sensor and the detailed physical basis of voltage-dependent activation in ion channels have not been determined. We now have identified conserved molecular rearrangements underlying two major voltage-dependent conformational changes during activation of divergent K+ channels, etherA-go-go (eag) and Shaker. Two conserved arginines of the S4 voltage sensor move sequentially into an extracellular gating pocket, where they interact with an acidic residue in S2. In eag, these transitions are modulated by a divalent ion that binds in the gating pocket. Conservation of key molecular details in the activation mechanism confirms that voltage sensors in divergent K+ channels share a common structure. Molecular modeling reveals that structural constraints derived from eag and Shaker specify the unique packing arrangement of transmembrane segments S2, S3, and S4 within the voltage sensor.