TY - JOUR TI - Regulation of Eag1 gating by its intracellular domains AU - Whicher, Jonathan R AU - MacKinnon, Roderick A2 - Yellen, Gary A2 - Boudker, Olga A2 - Yellen, Gary A2 - Swartz, Kenton Jon VL - 8 PY - 2019 DA - 2019/09/06 SP - e49188 C1 - eLife 2019;8:e49188 DO - 10.7554/eLife.49188 UR - https://doi.org/10.7554/eLife.49188 AB - Voltage-gated potassium channels (Kvs) are gated by transmembrane voltage sensors (VS) that move in response to changes in membrane voltage. Kv10.1 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 Kv11-12 channels. KW - voltage-gated potassium channel KW - electrophysiology KW - cryo-EM KW - CHO cells KW - HEK293S GnTI- KW - SF9 cells JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -