Engineering charge selectivity in model ion channels.
Most ion channel proteins exhibit some degree of charge selectivity, that is, an ability to conduct ions of one charge more efficiently than ions of the opposite charge. The structural origins of charge selectivity remain incompletely understood despite recent advances in the determination of cation-selective and anion-selective channel protein structures. Helix bundle channels formed via self-assembly of the peptide alamethicin provide a tractable model system for exploring the structural basis of charge selectivity. We synthesized covalently-linked alamethicin dimers, with amino acid substitutions at position 18 [lysine (Lys), arginine (Arg), glutamine (Gln), 2,3-diaminopropionic acid (Dpr)] in each helix, to assess the role of this position as a charge-selectivity determinant in alamethicin channels. Of the position 18 substitutions investigated, the Lys derivative exhibited the greatest degree of anion selectivity. Arg-containing channels were slightly less anion-selective than Lys. Interestingly, Dpr channels showed cation selectivity nearly equivalent to that exhibited by the neutral Gln derivative. We suggest that this result is due to a wider pore diameter that permits a greater number of counter-ions leading to enhanced charge screening and a lower effective side-chain positive charge.
Lougheed
Tyler
T
Department of Chemistry, 80 St George St University of Toronto, Toronto, Ontario, Canada M5S 3H6.
Zhang
Zhihua
Z
Andrew Woolley
G
G
Borisenko
Vitali
V
D000408:Alamethicin / Q000138:chemical synthesis* / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D019281:Dimerization; D007473:Ion Channels; D007476:Ionophores / Q000138:chemical synthesis* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000378:metabolism
D007473:Ion Channels; D007476:Ionophores; D010446:Peptide Fragments; D000408:Alamethicin