Structural Basis of Slow Activation Gating in the Cardiac IKs Channel ComplexStrutz-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
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
Department of Biochemistry I - Cation Channel Group
Ruhr University Bochum (Germany)
Tel. +49 234 32-24233, Fax +49 234 32-14034
Do you have an account?
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
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.