A MIXED HELIX-BETA-SHEET MODEL OF THE TRANSMEMBRANE REGION OF THE NICOTINIC ACETYLCHOLINE-RECEPTOR

We have modelled the transmembrane region of the alpha 7 nicotinic ace tylcholine receptor as a mixed alpha-helical/beta-sheet structure, The model was mainly based on the crystal structure of a pore-forming tox in, heat-labile enterotoxin. This is a pentameric protein having a cen tral pore or channel composed of five alpha-helices, one from each of the 5 B subunits that form this pentamer, The remainder of this struct ure is beta-sheet, loops and a short alpha-helix, not included in the model, The model uses this channel as a template to build the transmem brane region, from M1 to the middle of M3, The remainder of M3 and M4 were built de novo as alpha-helices, Great consideration was given to labelling data available for the transmembrane region, In general term s, the shape of the model agrees very well with that obtained independ ently by electron microscopic analysis and the secondary structure pre dicted by the model is in accord with that estimated independently by Fourier transform infrared spectroscopy, The M2 helical region of the model is only slightly kinked, contrary to what is inferred from elect ron microscopic analysis, but has the same overall shape and form, On the membrane face of the model, the presence of deep pockets may provi de the structural basis for the distinction between annular and non-an nular lipid binding sites, Also, the transmembrane region is clearly a symmetric in the direction perpendicular to the membrane, and this may have strong influence on the surrounding lipid composition of each le aflet of the cytoplasmic membrane.