Abstract
Voltage-sensing domains (VSDs) are integral membrane protein units that sense changes in membrane electric potential, and through the resulting conformational changes, regulate a specific function. VSDs confer voltage-sensitivity to a large superfamily of membrane proteins that includes voltage-gated Na\(^{+}\), K\(^{+}\), Ca\(^{2+}\) ,and H\(^{+}\) selective channels, hyperpolarization-activated cyclic nucleotide-gated channels, and voltage-sensing phosphatases. VSDs consist of four transmembrane segments (termed S1 through S4). Their most salient structural feature is the highly conserved positions for charged residues in their sequences. S4 exhibits at least three conserved triplet repeats composed of one basic residue (mostly arginine) followed by two hydrophobic residues. These S4 basic side chains participate in a state-dependent internal salt-bridge network with at least four acidic residues in S1–S3. The signature of voltage-dependent activation in electrophysiology experiments is a transient current (termed gating or sensing current) upon a change in applied membrane potential as the basic side chains in S4 move across the membrane electric field. Thus, the unique structural features of the VSD architecture allow for competing requirements: maintaining a series of stable transmembrane conformations, while allowing charge motion, as briefly reviewed here.
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This work was supported by the National Institutes of Health Grant GM86685. Anton computer time was provided by the National Center for Multiscale Modeling of Biological Systems (MMBioS) through Grant P41GM103712-S1 from the National Institutes of Health and the Pittsburgh Supercomputing Center (PSC). This work used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation Grant number ACI-1053575.
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Freites, J.A., Tobias, D.J. Voltage Sensing in Membranes: From Macroscopic Currents to Molecular Motions. J Membrane Biol 248, 419–430 (2015). https://doi.org/10.1007/s00232-015-9805-x
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DOI: https://doi.org/10.1007/s00232-015-9805-x