Structural changes during ion channel gating

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Abstract

Ion channels are generally multi-subunit complexes, with the ion conduction pathway formed at the subunit interface. In moving between the closed and open states, three structurally distinct channels, represented by the recently determined structures of a mechanosensitive, ligand-gated and K+ selective channel, all move transmembrane helices away from the central ion conduction pathway. In all three cases, this results in the displacement of a hydrophobic gate from the ion conduction pathway, freeing ion movement. The channels achieve this by moving the transmembrane helices as rigid bodies using three major types of motion: MscL tilts its helices, the nicotinic ACh receptor rotates its helices, and KirBac1.1 bends its helices. In all cases, the gating motions are likely to take place rapidly. These large and fast movements provide a possible explanation for why the conduction pathways of a wide range of different ion channels are formed at the interface between subunits.

Section snippets

Helix tilt

In response to a large drop in osmolarity, bacteria activate several non-selective channels. In Escherichia coli, the largest single channel conductance (∼2.5 nS) is due to opening of the mechanosensitive EcoMscL channel [2]. The crystal structure of the Mycobacterium tuberculosis MscL homologue (TbMscL) was captured in the closed state [3]. The channel consists of five identical subunits with two transmembrane helices (TM1 and TM2) per subunit (Figure 1). TM1 and TM2 are tilted ∼30° with

Helix rotation

A major family of ion channels is the ligand-gated channels. Opening and closing of these channels is regulated by the binding of ligands at a site that is not part of the ion conduction pathway. The nicotinic ACh receptor is one such example. This channel from the electric organ of the Torpedo ray consists of five subunits designated α (2 subunits), β, δ and γ. The ligand is known to bind to the extracellular domains at two sites formed at the α-subunit interfaces [8]. The extracellular

Helix bending

As a result of the wealth of structural data on K+ channels, gating for these channels can be described in detail. All K+ channels consist of four subunits that form an ion conduction pathway at the interface, as exemplified by the KcsA structure [17]. This central section forms the selectivity filter and ion conduction pathway and is essentially the same in all K+ channels. It comprises the outer helix, the turret, the pore helix, the selectivity filter and the inner helix. Box 1 describes the

Subunit interface

An interesting common feature among these three diverse channels is that the ion conduction pathway is formed at the interface between subunits. For these channels, a single transmembrane helix is crucial in controlling the diameter of the ion pathway and, as a consequence, determines whether the channel is in the closed or open state. For MscL it is TM1, for the nicotinic ACh receptor it is M2, and for KirBac1.1 it is the inner helix. In all three cases hydrophobic residues, located on these

Concluding remarks

One common feature of nearly all ion channels is that they are multi-subunit complexes. Surprisingly, for nearly all of the major ion channel families this results in the ion conduction pathway being located in the middle of the protein, formed by the common subunit interface. This applies to the large family of voltage-gated channels that are Na+, K+ or Ca2+ selective, the cyclic-nucleotide-gated channels, epithelial Na+ channels, P2X receptors, ACh receptors, inositol (1,4,5)-trisphosphate

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