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


The transduction of transmembrane electric fields into protein motion has an essential role in the generation and propagation of cellular signals. Voltage-sensing domains (VSDs) carry out these functions through reorientations of positive charges in the S4 helix. Here, we determined crystal structures of the Ciona intestinalis VSD (Ci-VSD) in putatively active and resting conformations. S4 undergoes an ~5-Å displacement along its main axis, accompanied by an ~60° rotation. This movement is stabilized by an exchange in countercharge partners in helices S1 and S3 that generates 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 enzymes and ion channels.

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Figure 1: Stabilizing two conformations of Ci-VSD by local field engineering.
Figure 2: Structure of Ci-VSD R217E in the activated (up) conformation.
Figure 3: The nature of S4 rearrangement in a lipid environment.
Figure 4: Structure of WT Ci-VSD in the resting (down) conformation.
Figure 5: Structural change between Ci-VSD WT and R217E.
Figure 6: A molecular mechanism of charge translocation in a voltage sensor.

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  • 23 February 2014

    In the version of this article initially published online, an incorrect affiliation was listed for Klaus Schulten. Klaus Schulten is affiliated with the Beckman Institute and Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA. In addition, in Figure 5c, one of the structures was incorrectly labeled. Kv1.2 ch is shown in purple in the left panel of Figure 5c.The errors have been corrected for the print, PDF and HTML versions of this article.


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We are thankful to K. Rajashankar and the staff at the NE-CAT 24-ID beamline as well as to R. Sanishvili and the staff at the GM/CA 23-ID beamline in the Advanced Photon Source, Argonne National Laboratory. We thank the Perozo, Bezanilla and Roux laboratories for illuminating discussions and invaluable experimental advice and A. Koide and S. Koide (University of Chicago) for the antibody library. We are grateful to E.J. Adams, R. Keenan, P. Rice and X. Yang for helpful crystallographic advice. The US National Resource provided Anton computer time for Biomedical Supercomputing and the Pittsburgh Supercomputing Center through grants RC2GM093307 and PSCA13070P (to E.P.) from the US National Institutes of Health. This work was supported in part by US National Institutes of Health grants R01-GM57846 (to E.P.), U54-GM74946 (to E.P.), R01-GM062342 (to B.R.), 9P41-GM104601 (to K.S.), U54-GM087519 (to K.S.) and 5R01-GM098243-02 (to K.S.) and a Beckman Postdoctoral Fellowship to A.S.

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E.P. and Q.L. designed experiments. Q.L. and S.W. performed biochemical experiments. M.P., Q.L. and A.K. selected Fab by phage-display methods. Q.L., S.W., R.E.H. and E.P. collected crystallographic data. Q.L. analyzed crystallographic data. D.M. and B.R. performed MD simulations to estimate the gating charge. A.S., R.M. and K.S. developed and applied the xMDFF method. C.A.V.-G. and Q.L. performed electrophysiological measurements. E.P. and Q.L. wrote the manuscript.

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Correspondence to Eduardo Perozo.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Ci-VSD R217E structure details at 2.5-Å resolution.

(a) The Ci-VSD-R217E+33F12_4 crystal belongs to space group P6522 and contains 12 complexes (6 homodimers) in the unit cell. The dimer is formed with a crystallographically related symmetry partner on a screw axis. (b) 2Fo-Fc electron density maps (σ=1.0) of Ci-VSD-R217E complex. The S4 segment is colored in red. (c) Close-up view of R217E structure. The side chains are well resolved at 2.5 Å resolution throughout Ci-VSD including the gating arginine residues (magenta) R223, R226, R229 and R232. (d) Three LDAO detergent molecules and one succinic acid molecule were resolved around S3-S4 loop region of R217E structure (yellow sticks).

Supplementary Figure 2 EPR spectra for all scanned residues.

Continuous wave EPR spectra of spin labeled single cysteine Ci-VSD-1-260 mutants on both WT (red) and R217E (black) background scanning the region 201-250. Each pair of spectra was normalized by double integration. The largest difference in spectra shape occurred at the end of the S4-phosphatse linker which is consistent with the heterogeneity of the linker from the crystal structures.

Supplementary Figure 3 Ci-VSD WT structure details at 3.6-Å resolution.

(a) Ci-VSD WT+39D10_18 crystal belongs to space group P1 and contains 4 complexes (2 dimers) per asymmetric unit. B. Backbone of Ci-VSD WT. (b) Cα is shown in sphere for the S4 arginines (blue to cyan) hydrophobic gasket (yellow) and counter charges (red). (c) 2Fo-Fc electron density maps (σ=1.0) of one representative WT+39D10_18 complex. The S4 segment and S4-phosphatase linker were colored in red. The backbone of Ci-VSD was well resolved. (d) Superposition of the four copies of the Ci-VSDWT+39D10_18 complex inside the P1 unit cell. Backbones for the three individual domains were aligned separately and overlapped with each other within the four copies (left). Dramatic differences showed up among the four complexes when they were aligned at Ci-VSD as a whole unit (right). The variation in the four variable domains is only 1~2 Å, but extends to ~12 Å among constant domains. This apparent flexibility comes from the relative position between individual structural domains, particularly between the constant and variable domains of the Fab. The individual transmembrane regions of Ci-VSD WT are shown to be essentially identical when superimposed. There is clear heterogeneity of S4-phosphtase linker in Ci-VSD-WT since it is resolved in only three out of four copies in the asymmetric unit (e), even though the interactions involved in S4 are the same among four copies.

Supplementary Figure 4 Evaluation structural models with experimental density map.

(a) 2Fo-Fc map (at σ=1.0, teal) for residues 196-244 of Ci-VSD WT (yellow ribbon) covering the top of S3, S3-S4 loop, entire S4 and S4-phosphatase linker. The R217E structure (white ribbon) with residues 196-236 was shown for comparison. The bulky residues distributed throughout the whole region were shown as F199, Y200, E205, R223 and F234. (b) The hypothetical two-click down model (red ribbon) shift the S4 helix 3-residue downward, in reference to Ci-VSD WT model (yellow ribbon). The resulting shorter S3-S4 loop obviously deviates away from the continuous electron density map (within the red circle) and proves itself an improper model for current data. 2Fo-Fc (at σ = 1.0, teal) and Fo-Fc (at σ = 3.0, white) maps of S4+linker for Ci-VSD-WT (c) and hypothetical Up-conformation model (d). The Up-conformation model shift S4 helix 3-residue upward which leaves unaccounted electron density after residue 244 the end of current crystallization construct for Ci-VSD, by both 2Fo-Fc and Fo-Fc maps. The map quality around linker 238-244 in hypothetical “up-state” model was shown in (e) carved at 10 Å around the linker. The positive difference map (Fo-Fc) at end of the linker (white region inside red circle) is clearly above noise level.

Supplementary Figure 5 A conceptual and technical workflow of xMDFF implementation.

It shows the flexible fitting of an atomic model into an iteratively updated electron density map synthesized from experimental diffraction data, and the phase information obtained from the up-to-date fitted model. (c) Improvements in R-free, MolProbity scores and percentage of Ramachandran favored conformations resulting from xMDFF refinements of six low-resolution (4-4.5Å) X-ray structures.

Supplementary Figure 6 Rotamer orientation of gating arginines is a common motif among voltage sensors.

A large span in the relative orientation of the arginine rotamers was clearly visible if the four gating arginine residues (R223: blue, R226: lilac, R229: teal and R232: cyan) were backbone aligned in the R217E structure. R229 lies horizontally inside the hydrophobic gasket and separates the intracellular and extracellular sides electrically. R223 and R226 point straight up above the electric field, while R232 points down below the electrical field. The span of arginine rotamers was most obvious in Ci-VSD, but is also present in other existing VSDs: KvAP, Kv1.2-2.1 chimera and NavAb (however, not in NavRh). This rotameric reorientation mechanism might be an additional contributor the total gating charge translocation in VSDs.

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Li, Q., Wanderling, S., Paduch, M. et al. Structural mechanism of voltage-dependent gating in an isolated voltage-sensing domain. Nat Struct Mol Biol 21, 244–252 (2014).

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