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Proton currents constrain structural models of voltage sensor activation.

Aaron L Randolph1,2, Younes Mokrab3, Ashley L Bennett1,2

  • 1Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, United States.

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Summary

The Hv1 proton channel

Keywords:
biophysicschannel gatingmembrane channelsnoneprotein structureproton transportstructural biologyvoltage sensor

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Area of Science:

  • Molecular and Cellular Biology
  • Biophysics
  • Ion Channel Physiology

Background:

  • The Hv1 proton channel is unique among voltage-sensor domain (VSD) proteins for its intrinsic aqueous proton (H+) conductance (GAQ).
  • Voltage-gated ion channels (VGCs) and voltage-sensor proteins (VSPs) can exhibit a resting-state H+ 'shuttle' conductance (GSH) upon mutation of conserved gating charge residues in the S4 helix.

Purpose of the Study:

  • To investigate whether the R1H mutation in Hv1 can reconstitute GSH without affecting GAQ.
  • To elucidate the distinct gating mechanisms and thermodynamic steps of GAQ and GSH in Hv1 activation.
  • To refine structural models of Hv1 activation and H+ transfer mechanisms.

Main Methods:

  • Site-directed mutagenesis of the Hv1 proton channel, specifically targeting the R1H residue and second-site mutations (D185A/H, N4R).
  • Electrophysiological recordings to measure proton conductance (GAQ and GSH).
  • Thermodynamic analysis of gating.
  • Computational modeling of VSD structures in resting and activated states.

Main Results:

  • The R1H mutation in Hv1 successfully reconstituted GSH while preserving GAQ.
  • Second-site mutations in S3 and S4 (D185A/H, N4R) allowed for experimental separation of GSH and GAQ gating.
  • GSH and GAQ gating represent distinct initial and final thermodynamic steps in the Hv1 activation pathway.
  • Mutational effects provided constraints for side-chain positions in resting- and activated-state VSD models.

Conclusions:

  • Hv1's unique H+ conductance mechanisms can be dissected through specific mutations.
  • The study provides a framework for understanding the structural basis of VSD activation and H+ transfer.
  • Distinct gating pathways for aqueous and shuttle proton conductances in Hv1 were identified.