Mechanism underlying delayed rectifying in human voltage-mediated activation Eag2 channel

Abstract

Voltage gradient is a general physical cue that regulates diverse biological function through voltage-gated ion channels. How voltage sensing mediates ion flows remains unknown at the molecular level. Here, we report six conformations of the human Eag2 (hEag2) ranging from closed, pre-open, open, and pore dilation but non-conducting states captured by cryo-electron microscopy (cryo-EM). These multiple states illuminate dynamics of selectivity filter and ion permeating pathway with delayed rectifier property and Cole-Moore effect at the atomic level. Mechanistically, a short S4-S5 linker is coupled with the constrict sites to mediate voltage transducing in a non-domain-swapped configuration, resulting transitions for constrict sites of F464s and Q472s from gating to open state stabilizing for voltage energy transduction. Meanwhile, an additional ion occupied at positions S6 potassium ion confers the delayed rectifier property and Cole-Moore effects. These results provide novel insight into voltage transducing and potassium current across membrane, and shed light on the long-sought Cole-Moore effects.