Abstract

Voltage-gated proton channels, HV1, trigger bioluminescence in dinoflagellates, enable calcification in coccolithophores, and play multifarious roles in human health. Because the proton concentration is minuscule, exquisite selectivity for protons over other ions is critical to HV1 function. The selectivity of the open HV1 channel requires an aspartate near an arginine in the selectivity filter (SF), a narrow region that dictates proton selectivity, but the mechanism of proton selectivity is unknown. Here we use a reduced quantum model to elucidate how the Asp–Arg SF selects protons but excludes other ions. Attached to a ring scaffold, the Asp and Arg side chains formed bidentate hydrogen bonds that occlude the pore. Introducing H3O+ protonated the SF, breaking the Asp–Arg linkage and opening the conduction pathway, whereas Na+ or Cl– was trapped by the SF residue of opposite charge, leaving the linkage intact, thus preventing permeation. An Asp–Lys SF behaved like the Asp–Arg one and was experimentally verified to be proton-selective, as predicted. Hence, interacting acidic and basic residues form favorable AspH0–H2O0–Arg+ interactions with hydronium but unfavorable Asp––X–/X+–Arg+ interactions with anions/cations. This proposed mechanism may apply to other proton-selective molecules engaged in bioenergetics, homeostasis, and signaling.

Highlights

  • The voltage-gated proton channel, HV1, has been implicated in numerous biological functions in humans[1]: charge compensation during the respiratory burst of phagocytes killing bacteria[2,3], pH homeostasis in airway epithelia[4], histamine secretion by basophils[5], and triggering sperm capacitation[6]

  • Since no 3D structure of HV1 in an open conformation has been solved, hypotheses on proton selectivity and conduction have been based on homology models derived from the open-state structures of voltage-gated sodium or potassium channels, which share only 13–19% sequence identity with hHV122

  • molecular dynamics (MD) simulations of human HV1 (hHV1) using as templates the open-state structures of the KvAP (1ORS)[23] and the Kv1.2-Kv2.1 paddle chimera (2R9R)[16] potassium channels predict a stable water wire in the open channel

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Summary

Introduction

The voltage-gated proton channel, HV1, has been implicated in numerous biological functions in humans[1]: charge compensation during the respiratory burst of phagocytes killing bacteria[2,3], pH homeostasis in airway epithelia[4], histamine secretion by basophils[5], and triggering sperm capacitation[6]. It was designed to maximize resemblance to the open HV1 SF and was constructed on the basis of the following considerations: At the narrowest, relatively dry region of the pore[14], the SF is lined by an aspartate (Asp[112] in hHV1), which is conserved in all known and putative HV11 This Asp interacts almost continuously with one of the three Arg residues in the S4 transmembrane segment in the open channel from MD simulations based on different homology models[14,15,16,17,29]. A positive point charge pulled through this double mutant in the broken configuration encountered a 10 kcal/mol barrier, but no barrier in the intact salt-bridge configuration[19] These findings indicate that the Asp–Arg interaction is essential to proton selectivity, it was incorporated into the SF model. Ions in bulk solution were not included in the SF model, since HV1 channels are notoriously indifferent to ionic strength[13], cations such as Ca2+ or Mg2+30,31, or anion species[31]

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