Miyazawa2003

Miyazawa2003 - Structure and gating mechanism of the...

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Unformatted text preview: Structure and gating mechanism of the acetylcholine receptor pore Atsuo Miyazawa * , Yoshinori Fujiyoshi & Nigel Unwin * RIKEN Harima Institute, 1-1-1 Kouto, Mikazuki-cho, Sayo, Hyogo 679-5148, Japan Department of Biophysics, Faculty of Science, Kyoto University, Oiwake, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK ........................................................................................................................................................................................................................... The nicotinic acetylcholine receptor controls electrical signalling between nerve and muscle cells by opening and closing a gated, membrane-spanning pore. Here we present an atomic model of the closed pore, obtained by electron microscopy of crystalline postsynaptic membranes. The pore is shaped by an inner ring of 5 a-helices, which curve radially to create a tapering path for the ions, and an outer ring of 15 a-helices, which coil around each other and shield the inner ring from the lipids. The gate is a constricting hydrophobic girdle at the middle of the lipid bilayer, formed by weak interactions between neighbouring inner helices. When acetylcholine enters the ligand-binding domain, it triggers rotations of the protein chains on opposite sides of the entrance to the pore. These rotations are communicated through the inner helices, and open the pore by breaking the girdle apart. The propagation of electrical signals between nerve cells and their targets takes place at the chemical synapse through the action of transmitter-gated ion channels. These fast-acting molecular switches are oligomeric proteins composed of two main functional parts: an extracellular, ligand-binding domain, and a gated, mem- brane-spanning pore. Neurotransmitter released from the nerve terminal enters the ligand-binding domain on the surface of the target cell, and triggers a transient conformational change that opens the gate in the membrane-spanning pore. Ions then flow selectively through the pore down their electrochemical gradients, giving rise to a change in membrane potential. The acetylcholine (ACh) receptor, at the nervemuscle synapse, is a member of a superfamily of transmitter-gated ion channels, which includes the serotonin 5-HT 3 , g-aminobutyric-acid (GABA A and GABA C ) and glycine receptors 1 . It has a cation-selective pore, delineated by a ring of five subunits ( a , a , b , g or 1 , d ), that opens upon binding of ACh to distant sites in the two a-subunits at or near the subunit interfaces 24 . There are four predicted membrane-spanning segments, M1M4, in each subunit. The second membrane-spanning segment, M2, shapes the lumen of the pore, and forms the gate of the closed channel. Although much information has been obtained about the roles of individual amino acids in affecting ion transport, and about their relative positions on the membrane-spanning segments, their detailed three-dimen-...
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Miyazawa2003 - Structure and gating mechanism of the...

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