The roles of serine and threonine sidechains in ion channels: a modelling study

Abstract

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.

Parallel helix bundles and ion channels: molecular modeling via simulated annealing and restrained molecular dynamics

“…Of particular interest in the context of the pore-lining residues of ion channel proteins (Sansom, 1992;Bertrand et al, 1993) is the variation in the pore radius as a function of z (Fig. 5).…”

Alamethicin and related peptaibols ? model ion channels

“…This motif is of particular importance with respect to the members of the nAChR superfamily, the central pores of which are formed by a bundle of five (Unwin 1989(Unwin , 1993Stroud et al 1990;Sansom 1992Sansom , 1993. It also may occur in other ion channel proteins.…”

Simplified Models of the Pore Domain of the Nicotinic Acetylcholine Receptor

“…The results are displayed in Figure 3 for representative structures from each ensemble. The minimum radius for the M2a model corresponds to the sidechain of Ser8, a candidate for solvation of permeant cations [5]. The minimum radius for the M2c model is at the sidechain of Leu1 1.…”