Structural dynamics determine voltage and pH gating in human voltage-gated proton channel

Voltage-gated ion channels are key players of electrical signaling in cells. As a unique subfamily, voltage-gated proton (Hv) channels are standalone voltage sensors without separate ion conductive pores. Hv channels are gated by both voltage and transmembrane proton gradient (i.e ∆pH), serving as acid extruders in most cells. Amongst their many functions, Hv channels are known for regulating the intracellular pH of human spermatozoa and compensating for the charge and pH imbalances caused by NADPH oxidases in phagocytes. Like the canonical voltage sensors, Hv channels are a bundle of 4 helices (named S1 through S4), with the S4 segment carrying 3 positively charged Arg residues. Extensive structural and electrophysiological studies on voltage-gated ion channels, in general, agree on an outwards movement of the S4 segment upon activating voltage, but the real-time conformational transitions are still unattainable. With purified human voltage-gated proton (hHv1) channels reconstituted in...