Β-Structure in the Membrane-Spanning Part of the Nicotinic Acetylcholine Receptor (Or How Helical Are Transmembrane Helices?) (original) (raw)

Abstract

MEMBRANE-BOUND RECEPTORS are classified according to the number of transmembrane helices they containL However, recent publications on the nicotinic acetylcholine receptor (nAChR), the prototype of four-transmembranehelix (4TM, type-l) receptors, question this method of classification 2-4. That the membrane-spanning domains of the 7TM (type-If) receptors are a-helical is supported largely by analogy with the light-driven proton pump bacteriorhodopsin. Evidence for exclusively helical secondary structures in the membranes of type-I (the ligand-gated ion channels) and type-Ill (the growth hormone receptors) receptors rests primarily on predictions rather than on facts. The question as to the secondary structure of transmembrane domains is by no means academic. The amino acid sequences immersed in the lipid bilayer serve two key functions: (I) they relay the extracellular signal to the cytoplasm, and (2) in the case of th~ type-I receptors they form the ion channel 5,e. A more thorough understanding of the structure of this functional domain may therefore lead to insights into the functional mechanism of receptors. (Of course, this structure comprises the amino acid sidechains in addition to the secondary structure.) The peripheral nAChR, involved in the transmission of signals from nerve to striated muscle, traditionally serves as a model for the superfamily of Ilgand-gated ion channels (for example, the nAChR, the glycine receptor, the GABA A receptor and the 5-HT 3 receptor) 7. A wealth of biochemical and biophysical data has been at'cumulated, from which models with increasing detail are emerging ~,8 (see Fig. I). Based on the well-established pentameric quaternary structure, the 4TM model postulates a bundle of 20 transmembrane a-helices. A constriction of the channel lumen has been detected 9 close to the cytoplasmic end of this bundle, which probably represents the selectivity filter ~°'n and gate of the pore. The distance between the membrane surface and the signal-receiving (agonist-binding) site

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