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J. Biol. Chem., Vol. 278, Issue 43, 42136-42148, October 24, 2003

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Structure of the HERG K⁺ Channel S5P Extracellular Linker

ROLE OF AN AMPHIPATHIC -HELIX IN C-TYPE INACTIVATION^*

Allan M. Torres, Paramjit S. Bansal, Margaret Sunde, Catherine E. Clarke¶, Jane A. Bursill¶, David J. Smith||, Asne Bauskin¶||, Samuel N. Breit¶||, Terence J. Campbell¶**, Paul F. Alewood, Philip W. Kuchel, and Jamie I. Vandenberg, Supported by NH&MRC Career Development Award 213415.¶**

From the School of Molecular and Microbial Biosciences, University of Sydney, New South Wales 2006, Australia, the Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland 4072, Australia, the ^¶Department of Medicine, University of New South Wales, New South Wales 2052, Australia, the ^||Centre for Immunology, St. Vincent's Hospital and University of New South Wales, Victoria Street, Sydney, New South Wales 2010, Australia, and the ^**Victor Chang Cardiac Research Institute, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia

The HERG K⁺ channel has very unusual kinetic behavior that includes slow activation but rapid inactivation. These features are critical for normal cardiac repolarization as well as in preventing lethal ventricular arrhythmias. Mutagenesis studies have shown that the extracellular peptide linker joining the fifth transmembrane domain to the pore helix is critical for rapid inactivation of the HERG K⁺ channel. This peptide linker is also considerably longer in HERG K⁺ channels, 40 amino acids, than in most other voltage-gated K⁺ channels. In this study we show that a synthetic 42-residue peptide corresponding to this linker region of the HERG K⁺ channel does not have defined structural elements in aqueous solution; however, it displays two well defined helical regions when in the presence of SDS micelles. The helices correspond to Trp⁵⁸⁵–Ile⁵⁹³ and Gly⁶⁰⁴–Tyr⁶¹¹ of the channel. The Trp⁵⁸⁵–Ile⁵⁹³ helix has distinct hydrophilic and hydrophobic surfaces. The Gly⁶⁰⁴–Tyr⁶¹¹ helix corresponds to an N-terminal extension of the pore helix. Electrophysiological studies of HERG currents following application of exogenous S5P peptides show that the amphipathic helix in the S5P linker interacts with the pore region of the channel in a voltage-dependent manner.

Received for publication, December 17, 2002 , and in revised form, July 22, 2003.

^* This work was supported in part by Grant 209547 from the National Health and Medical Research Council (to J. I. V. and T. J. C.), Grant A00104040 from the Australian Research Council (to P. W. K.), and a New South Wales Health Research and Development infrastructure grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental tables.

To whom correspondence should be addressed: Victor Chang Cardiac Research Institute, 384 Victoria St., Darlinghurst, NSW 2010, Australia. Tel.: 61-2-9295-8371; Fax: 61-2-9295-8390; E-mail: j.vandenberg{at}victorchang.unsw.edu.au.

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