The transport of ions across a cell membrane is something of a tricky business. The process involves moving a charged particle from one aqueous solution to another through the nonpolar, hydrophobic lipid bilayer of the cell membrane. Ion transport is critical to several basic cellular processes, and different ions (K+, Na+, Ca2+, Cl−) perform different, often specific tasks. In order to transport charged particles through an unfavorable environment, cell membranes possess specific ion channels. The study of ion channels, their functional regulation and how they achieve ion selectivity has advanced over the last several years, first with the first crystal structure of a bacterial K+ channel and then with insights into the basis of K+ selectivity. Now, in a recent issue of Nature, Dutzler et al. (Nature, 415, 287–294; 2002) report the first crystal structures of ClC chloride channels from Salmonella typhimurium and Escherichia coli.

Fig. prepared by R. MacKinnon and R. Dutzler.

The ClC Cl− channel is a homodimer with a two-fold axis of symmetry perpendicular to the plane of the cell membrane. Each of the individual, roughly triangular-shaped subunits contains its own ion channel, or pore. This 'double-barreled' arrangement was not surprising, based on previous biochemical studies of ClC Cl− channels. What is noteworthy, however, is the structure of the individual subunits (left). Each subunit consists of 18 α-helices. The subunits can be divided into two halves based on an unforeseen structural relationship between the N- and C-terminal sets of nine helices. The two halves interact in an antiparallel fashion with a pseudo two-fold symmetry axis parallel to the membrane. This interesting antiparallel architecture at once satisfies the constraints of embedding a protein in the low dielectric membrane and forms the basis for anion selectivity.

Ion selectivity is a critical feature of ion channels. In excitable cells such as muscle and nerve cells, cation permeability through anion channels (leak current) would greatly disturb normal excitation processes. Thus, the anion over cation selectivity of ClC Cl− channels must be absolute. As the structure of the ClC Cl− channel reveals (left), the helices in each subunit are arranged such that the N-terminal, partially positive ends (shown in blue) of three helices are oriented toward the membrane center creating an electrostatically favorable environment for anion (shown in red) binding — the selectivity filter. The partially negative end of the helix (red) is directed to the aqueous environment outside the membrane where the partial charge is stabilized through polar interactions.

Although the overall architecture of the K+ channel (right) is quite different from that of the ClC Cl− channel, helix dipoles are utilized in a similar fashion with reversed polarity. K+ channels consist of four identical subunits, containing a narrow selectivity filter region lined with electronegative main chain carbonyl oxygens. The K+ channel utilizes the helix dipole in concert with a large, water filled cavity to select for and stabilize K+ during transport, while the ClC Cl− channel apparently uses only the helix dipoles to confer anion selectivity. The end result is the same; the partial charges associated with the helix dipole create an electrostatically favorable environment for the charged particle within the membrane, while simultaneously avoiding the tight binding associated with full charges, allowing for rapid throughput. Thus, an expanding view of the use of helix dipoles in ion transport channels is emerging.