Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, Howard Hughes Medical Institute, New York, United States.
Elife. 2019 Sep 6;8:e49188. doi: 10.7554/eLife.49188.
Voltage-gated potassium channels (Ks) are gated by transmembrane voltage sensors (VS) that move in response to changes in membrane voltage. K10.1 or Eag1 also has three intracellular domains: PAS, C-linker, and CNBHD. We demonstrate that the Eag1 intracellular domains are not required for voltage-dependent gating but likely interact with the VS to modulate gating. We identified specific interactions between the PAS, CNBHD, and VS that modulate voltage-dependent gating and provide evidence that VS movement destabilizes these interactions to promote channel opening. Additionally, mutation of these interactions renders Eag1 insensitive to calmodulin inhibition. The structure of the calmodulin insensitive mutant in a pre-open conformation suggests that channel opening may occur through a rotation of the intracellular domains and calmodulin may prevent this rotation by stabilizing interactions between the VS and intracellular domains. Intracellular domains likely play a similar modulatory role in voltage-dependent gating of the related K11-12 channels.
电压门控钾通道（Ks）由跨膜电压传感器（VS）门控，VS 响应膜电压变化而移动。K10.1 或 Eag1 也有三个细胞内结构域：PAS、C 接头和 CNBHD。我们证明，Eag1 细胞内结构域不是电压门控所必需的，但可能与 VS 相互作用来调节门控。我们确定了 PAS、CNBHD 和 VS 之间的特定相互作用，这些相互作用调节电压依赖性门控，并提供证据表明 VS 运动使这些相互作用不稳定，从而促进通道开放。此外，这些相互作用的突变使 Eag1 对钙调蛋白抑制不敏感。钙调蛋白不敏感突变体在预开放构象中的结构表明，通道开放可能通过细胞内结构域的旋转发生，而钙调蛋白可能通过稳定 VS 和细胞内结构域之间的相互作用来阻止这种旋转。细胞内结构域可能在相关 K11-12 通道的电压依赖性门控中发挥类似的调节作用。
