X-ray crystal structure of voltage-gated proton channel

Structural and functional analysis reveal the resting state of the voltage-gated proton channel Hv1. Comparison with structures of voltage-sensing domains from other systems, captured in the activated state, will aid in understanding the mechanism of voltage sensing. The voltage-gated proton channel Hv1 (or VSOP) has a voltage-sensor domain (VSD) with dual roles of voltage sensing and proton permeation. Its gating is sensitive to pH and Zn 2+ . Here we present a crystal structure of mouse Hv1 in the resting state at 3.45-Å resolution. The structure showed a 'closed umbrella' shape with a long helix consisting of the cytoplasmic coiled coil and the voltage-sensing helix, S4, and featured a wide inner-accessible vestibule. Two out of three arginines in S4 were located below the phenylalanine constituting the gating charge–transfer center. The extracellular region of each protomer coordinated a Zn 2+ , thus suggesting that Zn 2+ stabilizes the resting state of Hv1 by competing for acidic residues that otherwise form salt bridges with voltage-sensing positive charges on S4. These findings provide a platform for understanding the general principles of voltage sensing and proton permeation.