Bundles of amphipathic transmembrane alpha-helices as a structural motif for ion-conducting channel proteins: studies on sodium channels and acetylcholine receptors.
Channel proteins are transmembrane symmetric (or pseudosymmetric) oligomers organized around a central ionic pore. We present here a molecular model of the pore forming structures of two channel proteins with different primary structures and oligomeric size: the voltage-sensitive sodium channel and the nicotinic cholinergic receptor. We report low-energy arrangements of alpha-helical bundles calculated by semiempiricial potential energy functions and optimization routines and further refined using molecular dynamics. The ion-conducting pore is considered to be a symmetric or pseudosymmetric homooligomer of 3-5 amphipathic alpha-helices arranged such that the polar residues line a central hydrophilic pathway and the apolar residues face the hydrophobic bilayer interior. The channel lining exposes either charged (Asp, Glu, Arg, Lys) or polar-neutral (Ser, Thr) residues. A bundle of four parallel helices constrained to C4 symmetry, the helix axis aligned with the symmetry axis, and the helices constrained to idealized dihedral angles, produces a structure with a pore of the size inferred for the sodium channel protein (area approximately 16 A2). Similarly, a pentameric array optimized with constraints to maintain C5 symmetry and backbone torsions characteristic of alpha-helices adopts a structure that appears well suited to form the lining of the nicotinic cholinergic receptor (pore area approximately 46 A2). Thus, bundles of amphipathic alpha-helices satisfy the structural, energetic, and dynamic requirements to be the molecular structural motif underlying the function of ionic channels.
Oiki
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S
Department of Neurosciences, Roche Institute of Molecular Biology, Nutley, New Jersey 07110.
Madison
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V
Montal
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D000595:Amino Acid Sequence; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011950:Receptors, Cholinergic / Q000737:chemistry* / Q000378:metabolism; D015222:Sodium Channels / Q000737:chemistry* / Q000378:metabolism
D008565:Membrane Proteins; D011950:Receptors, Cholinergic; D015222:Sodium Channels