Autonomous transmembrane segment S4 of the voltage sensor domain partitions into the lipid membrane

Venkataswarup Tiriveedhi, Melissa Miller, Peter Butko, Min Li

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


The S4 transmembrane segment in voltage-gated ion channels, a highly basic α helix, responds to changes in membrane potential and induces channel opening. Earlier work by others indicates that the S4 segment interacts with lipids in plasma membrane, but its mechanism is unclear. Working with synthetic tryptophan-labeled S4 peptides, we characterized binding of autonomous S4 to lipid membranes. The binding free energy (5.2 ± 0.2 kcal/mol) of the peptide-lipid interaction was estimated from the apparent dissociation constants, determined from the changes in anisotropy of tryptophan fluorescence induced by addition of lipid vesicles with 30 mol% phosphatidylglycerol. The results are in good agreement with the prediction based on the Wimley-White hydrophobicity scale for interfacial (IF) binding of an alpha-helical peptide to the lipid bilayer (6.98 kcal/mol). High salt inhibited the interaction, thus indicating that the peptide/membrane interaction has both electrostatic and non-electrostatic components. Furthermore, the synthetic S4 corresponding to the Shaker potassium channel was found to spontaneously penetrate into the negatively charged lipid membrane to a depth of about 9 Å. Our results revealed important biophysical parameters that influence the interaction of S4 with the membrane: they include fluidity, surface charge, and surface pressure of the membrane, and the α helicity and regular spacing of basic amino-acid residues in the S4 sequence.

Original languageEnglish (US)
Pages (from-to)1698-1705
Number of pages8
JournalBiochimica et Biophysica Acta - Biomembranes
Issue number7
StatePublished - Jul 2012
Externally publishedYes


  • Fluorescence spectroscopy
  • Potassium channel
  • Resonance energy transfer
  • S4
  • Small unilamellar vesicle
  • Voltage sensor domain

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Cell Biology


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