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Membrane proteins spotted in their native habitat

PSI-SGKB [doi:10.1038/fa_psisgkb.2009.58]
Featured Article - January 2010
Short description: A modest reshaping of the lipid bilayer allows water molecules to hydrate voltage-gating channels and focus the electrical field.

Effects of the voltage-sensing domain on a lipid bilayer as revealed by molecular dynamic simulation.

Atomic-resolution structures cannot tell the whole story of a membrane protein's activity. To really understand a channel's function, it has to be studied within its native setting — the lipid bilayer. A technical tour de force by Kenton Swartz, Steve White and colleagues reveals how voltage-sensing proteins subtly reshape the surrounding lipid bilayer.

Voltage-gated channels, such as potassium, sodium and calcium channels, open and close in response to a change in membrane voltage. Membrane-embedded helices S1–S4 sense electrical potential through charged amino-acid residues within helix S4. But how is the lipid bilayer — essentially a hydrophobic environment — able to accommodate this positive charge?

Until recently, the only way to answer this question was to use computational approaches. Molecular simulations suggested that the positive charges in helix S4 reorganize the surrounding membrane, but the effect of the whole sensor domain, S1–S4, was less clear and all these studies lacked experimental validation.

Membrane thinning

Swartz, White and colleagues examined the voltage-sensing domain of KvAP, a channel from the archeon Aeropyrum pernix. They prepared a homogeneous sample of this domain embedded in the lipid membrane and studied it using neutron diffraction, a technique that records average perturbations over the entire membrane plane.

Their data indicated that the bilayer remains largely intact around the S1–S4 module, although there is a thinning of the membrane directly around the protein of about 3 Å. It is possible that in certain locations, particularly in the area immediately surrounding the protein domains, the membrane is thinner than the average measured using neutron diffraction.

Water arrangement

Crevices in the potassium channel sensing domain, revealed during previous crystallographic experiments, have been suggested to reshape the electric field. To do this, they would need to be filled with water when the protein is embedded in the membrane, but until now, their hydration had not been measured.

To measure the hydration in the KvAP sensing domain, the team again used neutron diffraction; this time comparing the scattering from water and that from lipids with four deuterium atoms in the head-group region. As deuterated nuclei produce a positive scattering length, and hydrogen a negative one, deuterium can be easily detected. They found an extensive overlap of water and protein, suggesting that S1–S4 is hydrated.

Neutron diffraction can detect the overall distribution of water and protein in the bilayer but it cannot indicate whether water directly associates with the voltage sensors. So the authors used solid-state NMR spectroscopy to measure magnetization transfer from water to lipid by looking at 1H dipole–dipole interactions.

Their experiments indicated that water is closely associated with the protein within the bilayer and, taken together, these results suggest that the crevice in the sensing domain contains water when embedded in the membrane. When filled with water, this crevice would focus the electric field and would ensure that the charged residues remain charged and are able to move in response to membrane voltage.

The voltage sensor has probably evolved to interact with lipid molecules while keeping energetic and structural perturbations to the minimum. This set-up is likely to be relevant to other membrane proteins too. For example, G-protein-coupled receptors have binding sites for water-soluble ligands and perhaps these are hydrated in the membrane as well.

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  1. D. Krepkiy, M. Mihailescu, J. A. Freites, E. V. Schow, D. L. Worcester et al. Structure and hydration of membranes embedded with voltage-sensing domains.
    Nature 426, 473-479 (2009). doi:10.1038/nature08542

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