Structural basis for activation of voltage sensor domains in an ion channel TPC1

Significance This paper addresses how the structures of voltage-sensing domains within voltage-gated ion channels respond to physiological changes in electric potential across membranes. We report three new structures of TPC1 by cryo-EM and X-ray crystallography, two with voltage-sensing domains in intermediate activated conformations and a third structure representing the deactivated state under low cytoplasmic Ca 2+ . The intermediate states of the voltage sensor undergo significant rotation in the membrane plane and a twisting motion, with respect to our previously determined resting state, that alters access of gating charges from the inside to the outside of the membrane, with little vertical movement across the membrane. Together these structures suggest a general mechanism for the activation of voltage-gated ion channels.