Ion Channels Contain a Selectivity Filter Formed from Conserved Transmembrane a Helices and P Segments

All ion channels exhibit specificity for particular ions: K+ channels allow K+ but not closely related Na+ ions to enter, whereas Na+ channels admit Na+ but not K+. Determination of the three-dimensional structure of a bacterial K+ channel first revealed how this exquisite ion selectivity is achieved. As the sequences of other K+, Na+, and Ca2 + channels subsequently were determined, it became apparent that all such proteins share a common structure and probably evolved from a single type of channel protein.

Like all other K+ channels, bacterial K+ channels are built of four identical subunits symmetrically arranged around a central pore (Figure 7-15). Each subunit contains two membrane-spanning a helices (S5 and S6) and a short P (pore domain) segment that partly penetrates the membrane bilayer. In the tetrameric K+ channel, the eight transmembrane a helices (two from each subunit) form an "inverted teepee," generating a water-filled cavity called the vestibule in the central portion of the channel. Four extended loops that are part of the P segments form the actual ion-selectivity filter in the narrow part of the pore near the exoplasmic surface above the vestibule.

S6 a helices; they consist of a nonhellcal "turret," which lines the upper part of the pore; a short a helix; and an extended loop that protrudes into the narrowest part of the pore and forms the ion-selectivity filter. This filter allows K+ (purple spheres) but not other ions to pass. Below the filter is the central cavity or vestibule lined by the inner, or S6 a, helixes. The subunits in gated K+ channels, which open and close in response to specific stimuli, contain additional transmembrane helices not shown here. [See Y Zhou et al., 2001, Nature 414:43.]

Several types of evidence support the role of P segments in ion selection. First, the amino acid sequence of the P segment is highly homologous in all known K+ channels and different from that in other ion channels. Second, mutation of amino acids in this segment alters the ability of a K+ channel to distinguish Na+ from K+. Finally, replacing the P segment of a bacterial K+ channel with the homologous segment from a mammalian K+ channel yields a chimeric protein that exhibits normal selectivity for K+ over other ions. Thus all K+ channels are thought to use the same mechanism to distinguish K+ over other ions.

The ability of the ion-selectivity filter in K+ channels to select K+ over Na+ is due mainly to backbone carbonyl oxygens on glycine residues located in a Gly-Tyr-Gly sequence that is found in an analogous position in the P segment in every known K+ channel. As a K+ ion enters the narrow selectivity filter, it loses its water of hydration but becomes bound to eight backbone carbonyl oxygens, two from the extended loop in each P segment lining the channel (Figure 7-16a, left). As a result, a relatively low activation energy is required for passage of K+ ions through the channel. Because a dehydrated Na+ ion is too small to bind to all eight carbonyl oxygens that line the selectivity filter, the activation energy for passage of Na+ ions is relatively high (Figure 7-16a, right). This difference in activation energies favors

► Figure 7-16 Mechanism of ion selectivity and transport in resting K+ channels. (a) Schematic diagrams of K+ and Na+ ions hydrated in solution and in the pore of a K+ channel. As K+ ions pass through the selectivity filter, they lose their bound water molecules and become coordinated instead to eight backbone carbonyl oxygens, four of which are shown, that are part of the conserved amino acids in the channel-lining loop of each P segment. The smaller Na+ ions cannot perfectly coordinate with these oxygens and therefore pass through the channel only rarely. (b) High-resolution electron-density map obtained from x-ray crystallography showing K+ ions (purple spheres) passing through the selectivity filter. Only two of the diagonally opposed channel subunits are shown. Within the selectivity filter each unhydrated K+ ion interacts with eight carbonyl oxygen atoms (red sticks) lining the channel, two from each of the four subunits, as if to mimic the eight waters of hydration. (c) Interpretation of the electron-density map showing the two alternating states by which K+ ions move through the channel. In State 1, moving from the exoplasmic side of the channel inward one sees a hydrated K+ ion with its eight bound water molecules, K+ ions at positions 1 and 3 within the selectivity filter, and a fully hydrated K+ ion within the vestibule. During K+ movement each ion in State 1 moves one step inward, forming State 2. Thus in State 2 the K+ ion on the exoplasmic side of the channel has lost four of its eight waters, the ion at position 1 in State 1 has moved to position 2, and the ion at position 3 in State 1 has moved to position 4. In going from State 2 to State 1 the K+ at position 4 moves into the vestibule and picks up eight water molecules, while another hydrated K+ ion moves into the channel opening and the other K+ ions move down one step. [Part (a) adapted from C. Armstrong, 1998, Science 280:56. Parts (b) and (c) adapted from Y Zhou et al., 2001, Nature 414:43.]

(a) K+ and Na+ ions in the pore of a K+ channel (top view)

K+ in water

Na+ in water

K+ in water

Na+ in water

(b) K+ ions in the pore of a K+ channel (side view)

Exoplasmic face l oxygens

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