Structural biology

Highly charged meetings

When it comes to proteins and their environments, opposites repel. So how is the highly charged, polar helix of a transmembrane ion channel accommodated by a non-polar membrane? Easily, if the charges are buried.

Early in any biochemistry course, students are told that charged amino acids are not happy in hydrophobic (water-repelling) environments. Because the basic unit of biological membranes — the lipid bilayer — has a hydrophobic core, it follows that the α-helices of membrane-bound proteins should rarely contain charged amino acids. But there are exceptions, of which voltage-gated potassium channels form one class. On page 473 of this issue, Krepkiy et al.1 show that, contrary to textbook teachings, the highly charged α-helix present in these ion channels is fully compatible with a normal lipid bilayer.

Voltage-gated potassium channels are homotetramers — they assemble from four identical monomers, each of which contains six membrane-spanning α-helices. Two of the helices (S5 and S6) from each monomer come together in the tetrameric structure to form the pore through which potassium ions move across the membrane (Fig. 1). The remaining helices (S1 to S4) form voltage sensors, one for each monomer. A vital role is played by helix S4, which contains four or five positively charged amino-acid residues. It is these positive charges that allow the channel to sense a change in electrical potential across the membrane; subsequent movement of S4 leads to opening of the channel. But how can such a charged helix be accommodated in the hydrophobic environment of a lipid bilayer?

Figure 1: Structure of a voltage-gated potassium channel.

Voltage-gated potassium channels form pores in cell membranes through which potassium ions pass. The channel depicted here is a Kv2.1/Kv1.2 chimaeric channel9, viewed as though looking down on the membrane from the extracellular side (membrane not shown). Three of the four subunits are shown as surface plots in different shades of green, whereas the fourth subunit is shown in cartoon format. Most of the α-helices in the fourth subunit are depicted as red cylinders, but the first five positively charged amino-acid residues in helix S4 are shown in space-filling format. A potassium ion moving through the central pore is shown in purple. The channel has four voltage sensors (each composed of helices S1–S4) that are loosely attached to the central pore. The charged residues on S4 point in towards the other helices of the voltage sensor, and most are located in a water-filled cavity (not shown). Krepkiy and colleagues1 report that this means that the highly charged voltage sensor is fully compatible with the lipid bilayer that surrounds it in the native membrane.

Crystal structures of voltage-gated potassium channels have shown that the voltage sensors are only loosely attached to the central pore (Fig. 1, overleaf). In the first published structure2, which is recognized to be a distortion of the naturally occurring structure, the positive charges in S4 are partly exposed on the outer surface of the voltage sensor and are possibly in contact with the lipid bilayer. To see what effect such an exposed helix might have on a membrane, a computer model was generated of an isolated S4 helix in a lipid bilayer3. The model showed that the helix greatly distorts the bilayer, leading to the formation of hydrogen-bonded networks of water and lipid phosphate groups about each charged residue in the helix. The model also showed that the thickness of the bilayer's hydrophobic core close to the helix falls sharply from its normal value of 27 Å to about 10 Å. Such effects would be very unusual for a protein in a membrane because of the high energetic cost of distorting the bilayer4, and because the hydrophobic match between an undistorted lipid bilayer and a membrane protein is usually rather good5.

But does a complete voltage sensor, made up of helices S1 to S4, have the same effect on a lipid bilayer as an isolated S4 helix? The answer turns out to be no. Using neutron-diffraction techniques, Krepkiy and colleagues1 studied the properties of the bilayer surrounding a voltage sensor from a bacterial ion channel. They show that the bilayer remains intact and that it is only about 3 Å thinner than its normal thickness.

The authors' neutron-diffraction experiments measured the average thickness of the bilayer across the whole membrane plane. It is therefore possible that the bilayer close to the voltage sensor is thinner than the measured average. To find out whether this is the case, Krepkiy et al. performed molecular-dynamics simulations of their system. These models did indeed suggest that the thickness of the bilayer decreases by as much as 9 Å close to the voltage sensor. This conclusion must be treated with caution, however, because the authors' simulation also predicted that the unperturbed bilayer is about 4 Å thicker than the experimentally determined thickness6 (such models often overestimate the thickness of the bilayer). An earlier, coarse-grained molecular-dynamics simulation suggested that the effects of voltage sensors on bilayer thickness are small7.

The crystal structure of the potassium channel shown in Fig. 1 suggests a simple reason for the small effect that potassium-channel voltage sensors have on membranes: the charges on helix S4 are not actually exposed to the lipid bilayer. Instead, they are buried within the sensor structure, either occupying water-filled cavities or interacting with negatively charged residues in the S2 helix8. To confirm this, the authors performed further experiments that showed that the presence of the voltage sensor results in no measurable change in the amount of water in the lipid bilayer's core. The sensor is hydrated, however, as revealed by Krepkiy and colleagues' nuclear magnetic resonance studies1. The water molecules are probably located in crevices in the sensor, where they can hydrate some of the positively charged residues in S4, ensuring that these residues remain charged and so able to detect changes in potential across the membrane.

Overall, Krepkiy and colleagues' study is rather comforting — maybe the exceptions to the rules taught to biochemistry students aren't really exceptions after all. As with other membrane-bound proteins5, voltage-gated potassium channels must have evolved so that the packing preferences of the helices in the voltage sensor cause the sensor to adopt a structure that nicely matches that of the surrounding lipid bilayer. In this way, the hydrophobic lipid and the hydrophilic, charged sensor can meet without either having to change very much.


  1. 1

    Krepkiy, D. et al. Nature 462, 473–479 (2009).

    ADS  CAS  Article  Google Scholar 

  2. 2

    Jiang, Y. et al. Nature 423, 33–41 (2003).

    ADS  CAS  Article  Google Scholar 

  3. 3

    Freites, J. A., Tobias, D. J., von Heijne, G. & White, S. H. Proc. Natl Acad. Sci. USA 102, 15059–15064 (2005).

    ADS  CAS  Article  Google Scholar 

  4. 4

    Marsh, D. Biophys. J. 94, 3996–4013 (2008).

    ADS  CAS  Article  Google Scholar 

  5. 5

    Lee, A. G. Biochim. Biophys. Acta 1612, 1–40 (2003).

  6. 6

    Nagle, J. F. & Tristram-Nagle, S. Biochim. Biophys. Acta 1469, 159–195 (2000).

    CAS  Article  Google Scholar 

  7. 7

    Bond, P. J. & Sansom, M. S. P. Proc. Natl Acad. Sci. USA 104, 2631–2636 (2007).

    ADS  CAS  Article  Google Scholar 

  8. 8

    Chakrapani, S., Cuello, L. G., Cortes, D. M. & Perozo, E. Structure 16, 398–409 (2008).

    CAS  Article  Google Scholar 

  9. 9

    Long, S. B., Tao, X., Campbell, E. B. & MacKinnon, R. Nature 450, 376–382 (2007).

    ADS  CAS  Article  Google Scholar 

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Lee, A. Highly charged meetings. Nature 462, 420–421 (2009).

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