In voltage-activated potassium (Kv) channels, basic residues in S4 enable the voltage-sensing domain to move in response to membrane depolarization and thereby trigger the activation gate to open. In the X-ray structure of the KvAP channel, the S4 helix is located near the intracellular boundary of the membrane where it forms a "voltage-sensor paddle" motif with the S3b helix. It has been proposed that the paddle is lipid-exposed and that it translocates through the membrane as it activates. We studied the interaction of externally applied Hanatoxin with the voltage-sensor paddle in Kv channels and show that the toxin binds tightly even at negative voltages where the paddle is resting and the channel is closed. Moreover, measurements of gating charge movement suggest that Hanatoxin interacts with and stabilizes the resting paddle. These findings point to an extracellular location for the resting conformation of the voltage-sensor paddle and constrain its transmembrane movements during activation.
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