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Chapter 11 Biological Membranes and Transport

FIGURE 11-48 Structure and function of the K+ channel of Strep-tomyces lividans. (PDB ID 1BL8) (a) Viewed in the plane of the membrane, the channel consists of eight transmembrane helices (two from each of the four identical subunits), forming a cone with its wide end toward the extracellular space. The inner helices of the cone (lighter colored) line the transmembrane channel, and the outer helices interact with the lipid bilayer. Short segments of each subunit converge in the open end of the cone to make a selectivity filter. (b) This view perpendicular to the plane of the membrane shows the four subunits arranged around a central channel just wide enough for a single K+ ion to pass. (c) Diagram of a K+ channel in cross section, showing the structural features critical to function. (See also Fig. 11-49.)

FIGURE 11-48 Structure and function of the K+ channel of Strep-tomyces lividans. (PDB ID 1BL8) (a) Viewed in the plane of the membrane, the channel consists of eight transmembrane helices (two from each of the four identical subunits), forming a cone with its wide end toward the extracellular space. The inner helices of the cone (lighter colored) line the transmembrane channel, and the outer helices interact with the lipid bilayer. Short segments of each subunit converge in the open end of the cone to make a selectivity filter. (b) This view perpendicular to the plane of the membrane shows the four subunits arranged around a central channel just wide enough for a single K+ ion to pass. (c) Diagram of a K+ channel in cross section, showing the structural features critical to function. (See also Fig. 11-49.)

Backbone carbonyl oxygens form cage that fits K+ precisely, replacing waters of hydration sphere

Extracellular space

Alternating K+ sites (blue or green) occupied

Helix dipole stabilizes K+

Backbone carbonyl oxygens form cage that fits K+ precisely, replacing waters of hydration sphere

Extracellular space

Alternating K+ sites (blue or green) occupied

Helix dipole stabilizes K+

Helical Dipole

Cytosol

Large water-filled vestibule allows hydration of K+

Cytosol

K+ with hydrating water molecules

Large water-filled vestibule allows hydration of K+

K+ with hydrating water molecules

Each subunit has two transmembrane a helices as well as a third, shorter helix that contributes to the pore region. The outer cone is formed by one of the transmembrane helices of each subunit. The inner cone, formed by the other four transmembrane helices, surrounds the ion channel and cradles the ion selectivity filter.

Both the ion specificity and the high flux through the channel are understandable from what we know of the channel's structure. At the inner and outer plasma membrane surfaces, the entryways to the channel have several negatively charged amino acid residues, which presumably increase the local concentration of cations such as K+ and Na+. The ion path through the membrane begins (on the inner surface) as a wide, water-filled channel in which the ion can retain its hydration sphere. Further stabilization is provided by the short a helices in the pore region of each subunit, with the partial negative charges of their electric dipoles pointed at K+ in the channel. About two-thirds of the way through the membrane, this channel narrows in the region of the selectivity filter, forcing the ion to give up its hydrating water molecules. Carbonyl oxygen atoms in the backbone of the selectivity filter replace the water molecules in the hydration sphere, forming a series of perfect coordination shells through which the K+ moves. This favorable interaction with the filter is not possible for Na+, which is too small to make contact with all the poten tial oxygen ligands. The preferential stabilization of K+ is the basis for the ion selectivity of the filter, and mutations that change residues in this part of the protein eliminate the channel's ion selectivity.

There are four potential K+-binding sites along the selectivity filter, each composed of an oxygen "cage" that provides ligands for the K+ ions (Fig. 11-49). In the crystal structure, two K+ ions are visible within the selectivity filter, about 7.5 A apart, and two water molecules occupy the unfilled positions. K+ ions pass through the filter in single file; their mutual electrostatic repulsion most likely just balances the interaction of each ion with the selectivity filter and keeps them moving. Movement of the two K+ ions is concerted: first they occupy positions 1 and 3, then they hop to positions 2 and 4 (Fig. 11-48c). The energetic difference between these two configurations (1, 3 and 2, 4) is very small; energetically, the selectivity pore is not a series of hills and valleys but a flat surface, which is ideal for rapid ion movement through the channel. The structure of the channel appears to have been optimized during evolution to give maximal flow rates and high specificity.

The Neuronal Na+ Channel Is a Voltage-Gated Ion Channel

Sodium ion channels in the plasma membranes of neurons and of myocytes of heart and skeletal muscle sense

FIGURE 11-49 K+ binding sites in the selectivity pore of the K+ channel. (PDB ID 1J95) Carbonyl oxygens (red) of the peptide backbone in the selectivity filter protrude into the channel, interacting with and stabilizing a K+ ion passing through. These ligands are perfectly positioned to interact with each of four K+ ions, but not with the smaller Na+ ions. This preferential interaction with K+ is the basis for the ion selectivity. The mutual repulsion between K+ ions results in occupation of only two of the four K+ sites at a time (both green or both blue) and counteracts the tendency for a lone K+ to stay bound in one site. The combined effect of K+ binding to carbonyl oxygens and repulsion between K+ ions ensures that an ion keeps moving, changing positions within 10 to 100 ns, and that there are no large energy barriers to ion flow along the path through the membrane.

FIGURE 11-49 K+ binding sites in the selectivity pore of the K+ channel. (PDB ID 1J95) Carbonyl oxygens (red) of the peptide backbone in the selectivity filter protrude into the channel, interacting with and stabilizing a K+ ion passing through. These ligands are perfectly positioned to interact with each of four K+ ions, but not with the smaller Na+ ions. This preferential interaction with K+ is the basis for the ion selectivity. The mutual repulsion between K+ ions results in occupation of only two of the four K+ sites at a time (both green or both blue) and counteracts the tendency for a lone K+ to stay bound in one site. The combined effect of K+ binding to carbonyl oxygens and repulsion between K+ ions ensures that an ion keeps moving, changing positions within 10 to 100 ns, and that there are no large energy barriers to ion flow along the path through the membrane.

electrical gradients across the membrane and respond by opening or closing. These voltage-gated ion channels are typically very selective for Na+ over other monovalent or divalent cations (by factors of 100 or more) and have a very high flux rate (>107 ions/s). Normally (in the resting state) in the closed conformation, Na+ channels are opened—activated—by a reduction in the transmembrane electrical potential, then they undergo very rapid inactivation. Within milliseconds of the opening, the channel closes and remains inactive for many milliseconds. Activation followed by inactivation of Na+ channels is the basis for signaling by neurons (see Fig. 12-5).

The essential component of a Na+ channel is a single, large polypeptide (1,840 amino acid residues) organized into four domains clustered around a central channel (Fig. 11-50a, b), providing a path for Na+ through the membrane. The path is made Na+-specific by a "pore region" composed of the segments between transmembrane helices 5 and 6 of each domain, which fold into the channel. Helix 4 of each domain has a high density of positively charged residues; this segment is believed to move within the membrane in response to changes in the transmembrane voltage, from the "resting" potential of about —60 mV (inside negative) to about +30 mV. The movement of helix 4 triggers opening of the channel, and this is the basis for voltage gating (Fig. 11-50c).

Inactivation of the channel is thought to occur by a ball-and-chain mechanism. A protein domain on the cy-tosolic surface of the Na+ channel, the inactivation gate (the ball), is tethered to the channel by a short segment of the polypeptide (the chain) (Fig. 11-50b). This domain is free to move about when the channel is closed, but when it opens, a site on the inner face of the channel becomes available for the tethered ball to bind, blocking the channel. The length of the tether appears to determine how long an ion channel stays open; the longer the tether, the longer the open period. Inactivation of other ion channels may proceed by a similar mechanism.

The Acetylcholine Receptor Is a Ligand-Gated Ion Channel

Another very well-studied ion channel is the nicotinic acetylcholine receptor, essential in the passage of an electrical signal from a motor neuron to a muscle fiber at the neuromuscular junction (signaling the muscle to contract). (Nicotinic receptors were originally distinguished from muscarinic receptors by the sensitivity of the former to nicotine, the latter to the mushroom alkaloid muscarine. They are structurally and functionally different.) Acetylcholine released by the motor neuron diffuses a few micrometers to the plasma membrane of a myocyte, where it binds to the acetylcholine receptor. This forces a conformational change in the receptor, causing its ion channel to open. The resulting inward movement of positive charges depolarizes the plasma membrane, triggering contraction. The acetylcholine receptor allows Na+, Ca2 + , and K+ to pass through with equal ease, but other cations and all anions are unable to pass. Movement of Na+ through an acetylcholine receptor ion channel is unsaturable (its rate is linear with respect to extracellular [Na+]) and very fast—about 2 X 107 ions/s under physiological conditions.

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