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Original Paper

Structural Basis of Slow Activation Gating in the Cardiac IKs Channel Complex

Strutz-Seebohm N.1 · Pusch M.2 · Wolf S.3,4 · Stoll R.5 · Tapken D.6 · Gerwert K.3,4 · Attali B.7 · Seebohm G.1

Author affiliations

1Department of Biochemistry I - Cation Channel Group, Ruhr University, Bochum,2Istituto di Biofisica, Genova,3Department of Biophysics, CAS–Max-Planck Partner Institute for Computational Biology (PICB), Shanghai Institutes for Biological Sciences (SIBS), Shanghai,4Department of Biophysics, Ruhr University, Bochum,5Department of Biochemistry II - Biomolecular NMR Spectroscopy Group, Ruhr University, Bochum,6Department of Medicinal Chemistry - Biostructural Research Group, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen,7Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv

Corresponding Author

G. Seebohm

Department of Biochemistry I - Cation Channel Group

Ruhr University Bochum (Germany)

Tel. +49 234 32-24233, Fax +49 234 32-14034

E-Mail guiscard.seebohm@rub.de

Related Articles for ""

Cell Physiol Biochem 2011;27:443–452

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Accessory β-subunits of the KCNE gene family modulate the function of various cation channel α-subunits by the formation of heteromultimers. Among the most dramatic changes of biophysical properties of a voltage-gated channel by KCNEs are the effects of KCNE1 on KCNQ1 channels. KCNQ1 and KCNE1 are believed to form nativeIKs channels. Here, we characterize molecular determinants of KCNE1 interaction with KCNQ1 channels by scanning mutagenesis, double mutant cycle analysis, and molecular dynamics simulations. Our findings suggest that KCNE1 binds to the outer face of the KCNQ1 channel pore domain, modifies interactions between voltage sensor, S4-S5 linker and the pore domain, leading to structural modifications of the selectivity filter and voltage sensor domain. Molecular dynamics simulations suggest a stable interaction of the KCNE1 transmembrane α-helix with the pore domain S5/S6 and part of the voltage sensor domain S4 of KCNQ1 in a putative pre-open channel state. Formation of this state may induce slow activation gating, the pivotal characteristic of native cardiac IKs channels. This new KCNQ1-KCNE1 model may become useful for dynamic modeling of disease-associated mutant IKs channels.

© 2011 S. Karger AG, Basel

Article / Publication Details

First-Page Preview
Abstract of Original Paper

Accepted: March 30, 2011
Published online: June 15, 2011
Issue release date: June 2011

ISSN: 1015-8987 (Print)
eISSN: 1421-9778 (Online)

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