Add time:07/17/2019         Source:sciencedirect.com

The voltage-sensing domain (VSD) is a conserved structural module that regulates the gating of voltage-dependent ion channels in response to a change in membrane potential. Although structures of many VSD containing ion channels are now available, our understanding of the structural dynamics associated with gating transitions remains limited. In order to probe dynamics with site-specific resolution, we utilized NMR spectroscopy to characterize the VSD derived from Shaker potassium channel in LPPG micelles. The backbone dihedral angles predicted based on secondary chemical shifts using TALOS+ showed that the Shaker-VSD shares many structural features with the homologous Kv1.2/2.1 chimera, including a transition from α-helix to 310 helix in the C-terminal portion of the fourth transmembrane helix. Nevertheless, there are clear differences between the Shaker-VSD and Kv1.2/2.1 chimera in the S2-S3 linker and S3 transmembrane region, where the organization of secondary structure elements in Shaker-VSD appears to more closely resemble the KvAP VSD. Comparison of microsecond long molecular dynamics simulations of Kv 1.2-VSD in LPPG micelles and a POPC bilayer showed that LPPG micelles do not induce significant structural distortion in the isolated voltage-sensor. To assess the integrity of the tertiary fold, we directly probed the binding of BrET, a gating modifier toxin, and identified the location of the putative binding site. Our results suggest that the Shaker-VSD in LPPG micelles is in a native-like fold and is likely to provide valuable insights into the dynamics of voltage-gating and its regulation.

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