Hydrophobic plug functions as a gate in voltage-gated proton channels

Adam Chamberlin, Feng Qiu, Santiago Rebolledo, Yibo Wang, Sergei Y. Noskov, H. Peter Larsson

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


Voltage-gated proton (Hv1) channels play important roles in therespiratory burst, in pH regulation, in spermatozoa, in apoptosis,and in cancer metastasis. Unlike other voltage-gated cation channels, the Hv1 channel lacks a centrally located pore formed by theassembly of subunits. Instead, the proton permeation pathway inthe Hv1 channel is within the voltage-sensing domain of each sub-unit. The gating mechanism of this pathway is still unclear. Mutagenicand fluorescence studies suggest that the fourth transmembrane(TM) segment (S4) functions as a voltage sensor and that there isan outward movement of S4 during channel activation. Usingthermodynamic mutant cycle analysis, we find that the conservedpositively charged residues in S4 are stabilized by counterchargesin the other TM segments both in the closed and open states. Weconstructed models of both the closed and open states of Hv1channels that are consistent with the mutant cycle analysis. Thesestructural models suggest that electrostatic interactions betweenTM segments in the closed state pull hydrophobic residues togetherto form a hydrophobic plug in the center of the voltage-sensing domain. Outward S4 movement during channel activation inducesconformational changes that remove this hydrophobic plug andinstead insert protonatable residues in the center of the channelthat, together with water molecules, can form a hydrogen bondchain across the channel for proton permeation. This suggests thatsalt bridge networks and the hydrophobic plug function as thegate in Hv1 channels and that outward movement of S4 leads tothe opening of this gate.

Original languageEnglish (US)
Pages (from-to)E273-E282
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number2
StatePublished - 2014


  • Blocker
  • Molecular dynamics
  • Mutagenesis cycle
  • Voltage gating
  • VSOP

ASJC Scopus subject areas

  • General


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