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Pflugers Arch
2015 Aug 01;4678:1747-56. doi: 10.1007/s00424-014-1612-1.
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Interactions between the N-terminal tail and the gating machinery of hERG K⁺ channels both in closed and open/inactive states.
de la Peña P
,
Machín A
,
Fernández-Trillo J
,
Domínguez P
,
Barros F
.
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The N-terminal-most N-tail of the human ether-à-go-go-related gene (hERG) potassium channel is a crucial modulator of deactivation through its interactions with the S4-S5 loop and/or the C-linker/cNBD, leading to a stabilization of the channel's open state. Not only the N-terminal, but also the initial C-terminal region of the channel can modulate the transitions between the open and closed states either by direct or by indirect/allosteric interactions with the gating machinery. However, while a physical proximity of the N-tail to the gating machinery has been demonstrated in the closed state, data about their possible interaction in other channel conformations have been lacking. Using a site-directed cysteine mutagenesis and disulfide chemistry approach, we present here evidence that a physical proximity between the N-tail and the gating-related structures can also exist in channels held between pulses in the open/inactive state, highlighting the physiological and functional relevance of the direct interactions between the N-terminal tail and the S4-S5 loop and/or C-linker structures for modulation of channel.
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