Proton Conduction via Water Wire in the Hv1 Proton Channel

Abstract

The voltage-gated proton (Hv1) channel (2006, Science 312: 589; 2006, Nature 440: 1213) is homologous to the voltage-sensing domain (VSD) of voltage-gated ion channels, but unlike ion channels, Hv1 lacks a central pore domain. In Hv1, which forms a dimer, but also functions as a monomer, the VSD serves dual functions: it gates the proton current and also acts as the proton conduction pathway (2008, Neuron 58: 546; 2008, PNAS 105: 9111). In order to understand the proton conduction mechanism in Hv1, we have performed all-atom simulations of Hv1 and its mutants in a lipid bilayer in excess water to an aggregate trajectory length that exceeds 1 μs. To generate our Hv1 structural model, we used the VSD structure of the Kv1.2 paddle-chimera channel (2007, Nature 450: 376) as a template. Because the Hv1 S4 helix contains only three of the four highly conserved arginines (R1-R4) that are known to confer voltage sensitivity in VSDs of Kv channels, we generated two initial model configurations; one where the Hv1 S4 arginines were aligned to R1-R3 of the Kv VSD structure, and a second one where they were aligned to R2-R4. In both models, we observe a water wire that extends through the membrane, and is single file over a stretch of 8Å. In contrast, in a control simulation of the Kv chimera VSD, no waters are observed in the corresponding region. A network of charged residues that includes the S4 arginines as well as several acidic residues coordinates the Hv1 water wire. The presence of multiple basic and acidic residues in the region central to the water wire may explain the robustness of proton conduction in the presence of a variety of mutations (2010, NSMB 17: 869).