Salt-bridge switching underlies membrane voltage sensing

AUTHORS Tzur Paldi
ADMIN(S) Tzur Paldi
ABSTRACT Voltage sensing modules (VSMs) are specialized membrane proteins that change their conformation in response to changes in the electric potential across the cell membrane. The VSM is composed of four transmembrane helix segments (S1-S4), and its most striking feature is a conserved repetitive motif of a positively charged amino acid residue followed by two hydrophobic residues, within the fourth transmembrane segment (S4). It is generally accepted that the movement of the positively charged residues in the membrane electric field drives S4, relative to S1-S3. However, recent study showing the titratable nature of S4 arginines suggests that these arginines are not permanently charged, and changes in their ionization state may participate in the VSM voltage-sensing mechanism (Paldi, 2012 Here it is shown that the gating properties of the bacterial Na+ channel fit a model in which S4 arginines, salt bridged to acidic residues, are neutralized via voltage-dependent pKa shifts. A compatible mechanistic model that simulates the electrical properties of the VSM as those of a two-plate capacitor, shows that reorientation of a dipole moment, probably of water molecules, in the low dielectric septum of the VSM mediates these pKa shifts. The proposed model demonstrates the role of salt bridge formation in driving S4 and in preventing ion leaks (“omega” currents) through the VSM vestibule during S4 movement, while generating a capacitive gating current by means of proton relocation. This model agrees with major experimental aspects, and further reconciles them with the helical screw mechanism for S4 movement.
Ness Technologies Systems Group
Not Published
KEY WORDS Voltage gated ion channels, Electric field, Electrostatic interactions, NaChBac, pKa shift, Voltage-dependent ion channels, Voltage sensor domain, Voltage sensing

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