Structural models of NaChBac: Does the secondary structure of S4 change during gating?

Abstract

NaChBac is a prokaryotic 6TM tetrameric voltage-gated sodium channel with a locus point in homology space connecting channels from all major voltage gated channels superfamilies. The voltage-sensing domain of NaChBac exhibits the familiar RxxRxxR motif of S4 and conserved negative residues on S2 and S3. Thus, the voltage sensing mechanism of NaChBac is probably shared with other voltage gated channels. We have used the crystal structure of the Kv1.2/2.1 chimera to model NaChBac's open conformation and that of the MlotiK channel to model its closed conformation. In the closed MlotiK structure the first part of S4 forms a 310 helix and the last part forms an α helix, whereas in the open Kv1.2/2.1 structure the first part is an α helix while the rest is a 310 helix. This elastic type of transition between secondary structures during gating can explain some apparent discrepancies regarding the magnitude of S4 motion reported for several potassium channels. However, this type of transition alone is not sufficient to explain the large gating charge movement reported for NaChBac and other channels. To account for this, we have incorporated the α-310 transition into the “helical screw model” in which the α-helix part of S4 moves in a screw-like fashion while the 310 part of S4 moves in a simple axial translation. In our models four positively charged residues of S4 moves outwardly during activation across a transition barrier formed by highly conserved hydrophobic residues on S1, S2, and S3. S4 movement is coupled to opening of the activation gate formed by S6 through interactions with the segment linking S4 to S5. Consistencies of our models with experimental studies of the NaChBac and Kv channels will be discussed.