Structure and hydration of membranes embedded with voltage-sensing domains

Abstract

Despite the growing number of atomic-resolution membrane protein structures, direct structural information about proteins in their native membrane environment is scarce. This problem is particularly relevant in the case of the highly-charged S1–S4 voltage-sensing domains responsible for nerve impulses, where interactions with the lipid bilayer are critical for the function of voltage-activated potassium channels. Here we use neutron diffraction, solid-state nuclear magnetic resonance spectroscopy, and molecular dynamics simulations to investigate the structure and hydration of bilayer membranes containing S1–S4 voltage-sensing domains. Our results show that voltage sensors adopt transmembrane orientations, cause a modest reshaping of the surrounding lipid bilayer, and that water molecules intimately interact with the protein within the membrane. These structural findings reveal that voltage sensors have evolved to interact with the lipid membrane while keeping the energetic and structural perturbations to a minimum, and that water penetrates into the membrane to hydrate charged residues and shape the transmembrane electric field.

Structure and dynamics of cationic membrane peptides and proteins: Insights from solid‐state NMR

“…42 This result is consistent with neutron diffraction of the KvAP VSD. 122 REDOR experiments further indicate that the second Arg has a short Cf distance of 4.6 Å to the lipid 31 P, thus the same guanidinium-phosphate interaction seen in AMPs and CPPs also exist in the S4 helix. This topology and lipid-peptide interaction suggest that the S4 amino acid sequence plays a more important role than previously thought for determining the membrane topology of the gating segment, possibly without requiring interhelical protein-protein interactions.…”

Functional diversity of potassium channel voltage-sensing domains

“…One of the big surprises of the past decade is the discovery that these VSDs can adopt a stable conformation in the absence of the rest of the channel, having functional properties in the absence of the pore domain 7,8 and can be used to gate pore domains of different channels. [9][10][11] In fact, VSDs exist as independent gene products, coupled to other kinds of proteins, as demonstrated by the voltage-sensitive phosphatases 12 and can even mediate proton transport, as shown in the voltage-sensitive proton channels.…”

Mechanism of atomic force microscopy imaging of three-dimensional hydration structures at a solid-liquid interface

“…Hydration plays fundamental roles in biomolecular functions [1][2][3], crystal growth [4], soil wetting [5], and catalytic reactions [6]. Despite the wide success of diffraction and spectroscopy techniques in investigating hydration structures at the nanoscale [7][8][9][10][11][12][13], molecular level detail of water distributions at critical inhomogeneous interfaces remains elusive.…”