The hERG channel has an unusually long âS5âP linkerâ (residues 571â613) that lines the outer mouth of the pore. Previously,
we have shown that residues along this S5âP linker are critical ...for the fast-inactivation process and K + selectivity of the hERG channel. Here we used several approaches to probe the structure of this S5âP linker and its interactions
with other domains of the hERG channel. Circular dichroism and NMR analysis of a synthetic hERG S5âP linker peptide suggested
that this linker is quite dynamic: its central region (positions 583â593) can be unstructured or helical, depending on whether
it is immersed in an aqueous phase or in contact with a hydrophobic environment. Cysteine introduced into positions 583â597
of the S5âP linker can form intersubunit disulphide bonds, and at least four of them (at 584, 585, 588 and 589) can form disulphide
bonds with counterparts from neighbouring subunits. We propose that the four S5âP linkers in a hERG channel can engage in
dynamic conformational changes during channel gating, and interactions between S5âP linkers from neighbouring subunits contribute
importantly to channel inactivation.
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