The structure of the M2 channel-lining segment from the nicotinic acetylcholine receptor.
The structures of functional peptides corresponding to the predicted channel-lining M2 segment of the nicotinic acetylcholine (AChR) were determined using solution NMR experiments on micelle samples, and solid-state NMR experiments on bilayer samples. The AChR M2 peptide forms a straight transmembrane alpha-helix, with no kinks. M2 inserts in the lipid bilayer at an angle of 12 degrees relative to the bilayer normal, with a rotation about the helix long axis such that the polar residues face the N-terminus of the peptide, which is assigned to be intracellular. A molecular model of the AChR channel pore, constructed from the solid-state NMR 3-D structure of the AChR M2 helix in the membrane assuming a pentameric organization, results in a funnel-like architecture for the channel with the wide opening on the N-terminal intracellular side. A central narrow pore has a diameter ranging from about 3.0 A at its narrowest, to 8.6 A at its widest. Nonpolar residues are predominantly on the exterior of the bundle, while polar residues line the pore. This arrangement is in fair agreement with evidence collected from permeation, mutagenesis, affinity labeling and cysteine accessibility measurements. A pentameric M2 helical bundle may, therefore, represent the structural blueprint for the inner bundle that lines the channel of the nicotinic AChR.
Montal
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Section of Neurobiology, Division of Biology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0366, USA. mmontal@ucsd.edu
Opella
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D000818:Animals; D006801:Humans; D007473:Ion Channels / Q000737:chemistry*; D008051:Lipid Bilayers / Q000032:analysis*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008565:Membrane Proteins / Q000737:chemistry*; D008823:Micelles; D008958:Models, Molecular; D018272:Porins / Q000737:chemistry; D011978:Receptors, Nicotinic / Q000737:chemistry*
D007473:Ion Channels; D008051:Lipid Bilayers; D008565:Membrane Proteins; D008823:Micelles; D018272:Porins; D011978:Receptors, Nicotinic