TCB Publications - Abstract

Qufei Li, Sherry Wanderling, Marcin Paduch, David Medovoy, Abhishek Singharoy, Ryan McGreevy, Carlos Villalba-Galea, Raymond E. Hulse, Benoit Roux, Klaus Schulten, Anthony Kossiakoff, and Eduardo Perozo. Structural mechanism of voltage-dependent gating in an isolated voltage-sensing domain. Nature Structural & Molecular Biology, 21:244-252, 2014. (PMC: 4116111)

LI2014 The transduction of transmembrane electric fields into protein motion plays an essential role in the generation and propagation of cellular signals. Voltage-sensing domains (VSD) carry out these functions through reorientations of S4 helix with discrete gating charges. Here, crystal structures of the VSD from Ci-VSP were determined in both, active (Up) and resting (Down) conformations. The S4 undergoes a $\sim$5 Å displacement along its main axis accompanied by a $\sim$60$^{\circ}$ rotation, consistent with the helix-screw gating mechanism. This movement is stabilized by a change in countercharge partners in helices S1 and S3, generating an estimated net charge transfer of $\sim$1 e$_o$. 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 cellular activities.

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