Metal-ion bridge constraints and molecular modeling reveal that the S4 segment of the voltage-sensor domain slides at least 12 Å along its axis to open the channel.
Provides a detailed molecular model of intermediate conformations during voltage-sensor domain gating in potassium channels.
Voltage-gated ion channels open and close in response to changes in membrane potential, thereby enabling electrical signaling in excitable cells. The voltage sensitivity is conferred through four voltage-sensor domains (VSDs) where positively charged residues in the fourth transmembrane segment (S4) sense the potential. While an open state is known from the Kv1.2/2.1 X-ray structure, the conformational changes underlying voltage sensing have not been resolved. We present 20 additional interactions in one open and four different closed conformations based on metal-ion bridges between all four segments of the VSD in the voltage-gated Shaker K channel. A subset of the experimental constraints was used to generate Rosetta models of the conformations that were subjected to molecular simulation and tested against the remaining constraints. This achieves a detailed model of intermediate conformations during VSD gating. The results provide molecular insight into the transition, suggesting that S4 slides at least 12 Å along its axis to open the channel with a 3(10) helix region present that moves in sequence in S4 in order to occupy the same position in space opposite F290 from open through the three first closed states.
Henrion et al. (Wed,) conducted a other in Voltage-gated ion channel gating. Cd2+ metal-ion bridges and cysteine mutagenesis vs. Control solution / Wild-type was evaluated on Conformational changes in voltage-sensor domains. Metal-ion bridge constraints and molecular modeling reveal that the S4 segment of the voltage-sensor domain slides at least 12 Å along its axis to open the channel.