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

Abstract

SUMMARY 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 ~5 Å displacement along its main axis accompanied by a ~60o 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 ~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 cellular activities.

Bacterial Voltage-Gated Sodium Channels (BacNaVs) from the Soil, Sea, and Salt Lakes Enlighten Molecular Mechanisms of Electrical Signaling and Pharmacology in the Brain and Heart

“…6 c-d) 39; 97 . This difference is reminiscent of the observed VSD disengagement from the PD upon channel closure in simulations of Kv1.2/2.1 chimera in lipid membranes 160 and would seem to be in line with the independent character of the VSDs with respect to the overall protein structure 28; 129; 131; 142; 161 . Such displacements raise interesting questions about the exact functional states of the full length BacNa V structures, how there can be strong coupling between the internal motions of S4 within the VSD in response to voltage, and whether such global VSD motions have a role in voltage sensing 146 .…”

“…When all of the VSD coordinates are extracted from the BacNav structures and compared to the VSDs from Kv channels 28; 71; 86 , the proton gated channel (H V 1) 141 , and the voltage-sensitive phosphatase (VSP) 142 , a number of general conclusions can be made. First, at a gross level, all VSD structures are essentially identical and share a conserved structural core independent of their amino acid sequence or functional state (Fig.…”

“…Fourth, the S4 segment is in an entirely α-helical conformation in VSDs that have been cut away from the rest of their native sequence (i.e. KvAP 28 , Hv1 141 , and Ci-VSP 142 ). By contrast, VSDs that are still attached to their natural payloads all display some mixture of α-helix and 3 10 -helix along their S4 segments.…”

Functional diversity of potassium channel voltage-sensing domains

“…Almost simultaneously reported, the structures of the proton channel Hv1 and the voltage-sensitive phosphatase, were solved by X-ray diffraction. 8,31,32 Remarkably, the structure of CiVSP was obtained in putative activated and resting states, while the structure of Hv1 seems to be of a resting state.…”

Particle-based membrane model for mesoscopic simulation of cellular dynamics

“…As an example, consider endocytosis and exocytosis at plasma membranes 2 . While all-atom molecular simulations are extremely successful for the study of individual macromolecules and small complexes [3][4][5][6][7][8][9] and can reach thermodynamics and kinetics at very long timescales with the aid of enhanced sampling methods and Markov state modeling 7,[10][11][12][13][14][15][16][17][18] , they have severe limitations in terms of system sizes that can be sampled exhaustively 19 . Even for the simple case of equilibrating micron-sized biomembranes, a blind scale up in all-atom molecular dynamics would be out of reach of computational power for a) Corresponding author; Electronic mail: mohsen.sadeghi@fu-berlin.de b) Electronic mail: thomas.weikl@mpikg.mpg.de c) Corresponding author; Electronic mail: frank.noe@fu-berlin.de decades to come 20 .…”