The roles of serine and threonine sidechains in ion channels: a modelling study.
The ion channel of the nicotinic acetylcholine receptor (nAChR) is believed to be lined by transmembrane M2 helices. A "4-8-12" sequence motif, comprising serine (S) or threonine (T) residues at positions 4, 8 and 12 of M2, is conserved between different members, anion and cation selective, of the nAChR superfamily. Parallel bundles of 4-8-12 motif-containing helices are considered as simplified models of ion channels. The relationship between S and T sidechain conformations and channel-ion interactions is explored via evaluation of interaction energies of K+ and of Cl- ions with channel models. Energy calculations are used to determine optimal chi 2 (C alpha-C beta-O gamma-H gamma) values in the presence of K+ or Cl- ions. 4-8-12 motif-containing bundles may form favourable interactions with either cations or anions, dependent upon the chi 2 values adopted. Parallel-helix and tilted-helix bundles are considered, as are heteromeric models designed to mimic the Torpedo nAChR. The main conclusion of the study is that conformational flexibility at chi 2 enables both S and T residues to form favourable interactions with anions or cations. Consequently, there is apparently no difference between S and T residues in their interactions with permeant ions, which suggests that the presence of T vs. S residues within the 4-8-12 motif is not a major mechanism whereby anion/cation selectivity may be generated. The implications of these studies with respect to more elaborate models of nAChR and related receptors are considered.
Sansom
M S
MS
Laboratory of Molecular Biophysics, University of Oxford, UK.
D000595:Amino Acid Sequence; D000818:Animals; D002151:Calorimetry; D006860:Hydrogen Bonding; D007473:Ion Channels / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D011963:Receptors, GABA-A / Q000737:chemistry; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry; D011978:Receptors, Nicotinic / Q000737:chemistry; D011985:Receptors, Serotonin / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D012694:Serine; D013912:Threonine; D014101:Torpedo
D007473:Ion Channels; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D011985:Receptors, Serotonin; D013912:Threonine; D012694:Serine