The N-terminal tail of hERG contains an amphipathic alpha-helix that regulates channel deactivation

Ng, Chai Ann, Hunter, Mark J., Perry, Matthew D., Mobli, Mehdi, Ke, Ying, Kuchel, Philip W., King, Glenn F., Stock, Daniela and Vandenberg, Jamie I. (2011) The N-terminal tail of hERG contains an amphipathic alpha-helix that regulates channel deactivation. PLoS One, 6 1: e16191.1-e16191.9. doi:10.1371/journal.pone.0016191

Author Ng, Chai Ann
Hunter, Mark J.
Perry, Matthew D.
Mobli, Mehdi
Ke, Ying
Kuchel, Philip W.
King, Glenn F.
Stock, Daniela
Vandenberg, Jamie I.
Title The N-terminal tail of hERG contains an amphipathic alpha-helix that regulates channel deactivation
Formatted title
The N–terminal tail of hERG contains an amphipathic α–helix that regulates channel deactivation
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2011-01-13
Sub-type Article (original research)
DOI 10.1371/journal.pone.0016191
Open Access Status DOI
Volume 6
Issue 1
Start page e16191.1
End page e16191.9
Total pages 9
Editor Vladimir N. Uversky
Place of publication San Francisco, CA, U.S.A.
Publisher Public Library of Science
Language eng
Formatted abstract
The cytoplasmic N–terminal domain of the human ether–a–go–go related gene (hERG) K+ channel is critical for the slow deactivation kinetics of the channel. However, the mechanism(s) by which the N–terminal domain regulates deactivation remains to be determined. Here we show that the solution NMR structure of the N–terminal 135 residues of hERG contains a previously described Per–Arnt–Sim (PAS) domain (residues 26–135) as well as an amphipathic α–helix (residues 13–23) and an initial unstructured segment (residues 2–9). Deletion of residues 2–25, only the unstructured segment (residues 2–9) or replacement of the α–helix with a flexible linker all result in enhanced rates of deactivation. Thus, both the initial flexible segment and the α–helix are required but neither is sufficient to confer slow deactivation kinetics. Alanine scanning mutagenesis identified R5 and G6 in the initial flexible segment as critical for slow deactivation. Alanine mutants in the helical region had less dramatic phenotypes. We propose that the PAS domain is bound close to the central core of the channel and that the N–terminal α–helix ensures that the flexible tail is correctly orientated for interaction with the activation gating machinery to stabilize the open state of the channel.
Keyword K+ channels
Potassium channel
PAS domain
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 46 times in Thomson Reuters Web of Science Article | Citations
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Created: Sun, 27 Feb 2011, 10:02:52 EST