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


Carlos A. Villalba-Galea: 0000-0002-6489-4651

Document Type

Conference Presentation

Conference Title/Conference Publication

Biophysical Journal


Biophysical Society 57th Annual Meeting


Philadelphia, PA

Conference Dates

February 2-6, 2013

Date of Presentation







2, Supplement 1



First Page



The voltage-sensing domain (VSD) is a common scaffold responsible for the transduction of transmembrane electric fields into protein motion. They play an essential role in the generation and propagation of cellular signals driven by voltage gated ion channels, voltage sensitive enzymes and proton channels. All available VSD structures are thought to represent the activated conformation of the sensor due to the overall structural similarities and the mid-point of the voltage dependence of activation curves. Yet, in the absence of a resting state structure, the mechanistic details of voltage sensing remain controversial. The voltage dependence of the VSD from Ci-VSP (Ci-VSD) is dramatically right shifted, so that at 0 mV it presumably populates the putative resting state. We have determined crystal structures of the Ci-VSP voltage sensor in both active (Up) and resting (Down) conformations, between which the S4 undergoes a ∼5 Å displacement along its main axis with an accompanying 55-90o rotation resembling the basic helix-screw mechanism of gating. In the process, the gating charges change position relative to a “hydrophobic gasket” that electrically separates intra and extracellular compartments. This movement is stabilized by an exchange in countercharge partners in helices S1 and S3, for an estimated net charge movement of ∼1 eo. EPR spectroscopic measurements confirm the limited nature of S4 movement in a membrane environment. These results provide an explicit mechanism of voltage sensing in diverse voltage dependent cellular responses.