Title

Structural mechanism of voltage-dependent gating in an isolated voltage-sensing domain

ORCiD

0000-0002-6489-4651

Document Type

Article

Publication Title

Nature Structural & Molecular Biology

ISSN

1545-9985

Volume

21

Issue

3

DOI

10.1038/nsmb.2768

First Page

244

Last Page

252

Publication Date

3-1-2014

Abstract

The transduction of transmembrane electric fields into protein motion has an essential role in the generation and propagation of cellular signals. Voltage-sensing domains (VSDs) carry out these functions through reorientations of positive charges in the S4 helix. Here, we determined crystal structures of the Ciona intestinalis VSD (Ci-VSD) in putatively active and resting conformations. S4 undergoes an ~5-Å displacement along its main axis, accompanied by an ~60° rotation. This movement is stabilized by an exchange in countercharge partners in helices S1 and S3 that generates an estimated net charge transfer of ~1 eo. Gating charges move relative to a ''hydrophobic gasket' that electrically divides intra- and extracellular compartments. EPR spectroscopy confirms the limited nature of S4 movement in a membrane environment. These results provide an explicit mechanism for voltage sensing and set the basis for electromechanical coupling in voltage-dependent enzymes and ion channels.