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J Biol Chem, Vol. 274, Issue 50, 35521-35525, December 10, 1999

NMR Structure and Functional Characteristics of the Hydrophilic N Terminus of the Potassium Channel -Subunit Kv1.1^*

Ralph Wissmann, Thomas Baukrowitz, Hubert Kalbacher^§, Hans Robert Kalbitzer^¶, J. Peter Ruppersberg, Olaf Pongs, Christoph Antz^**, and Bernd Fakler^§§

From the  Department of Physiology II, University of Tübingen, Ob dem Himmelreich 7, 72074 Tübingen, Germany, ^§ Institute of Physiological Chemistry, University of Tübingen, Ob dem Himmelreich 7, 72074 Tübingen, Germany, ^¶ Department of Biophysics and Physical Biochemistry, University of Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany, ^** Otogene AG, Vor dem Kreuzberg 17, 72074 Tübingen, Germany, and  Zentrum für Molekulare Neurobiologie Hamburg, Falkenried 94, 20251 Hamburg, Germany

Rapid N-type inactivation of voltage-dependent potassium (Kv) channels controls membrane excitability and signal propagation in central neurons and is mediated by protein domains (inactivation gates) occluding the open channel pore from the cytoplasmic side. Inactivation domains (ID) are donated either by the pore-forming -subunit or certain auxiliary -subunits. Upon coexpression, Kv1.1 was found to endow non-inactivating members of the Kv1 family with fast inactivation via its unique N terminus. Here we investigated structure and functional properties of the Kv1.1 N terminus (amino acids 1-62, N-(1-62)) using NMR spectroscopy and patch clamp recordings. N-(1-62) showed all hallmarks of N-type inactivation: it inactivated non-inactivating Kv1.1 channels when applied to the cytoplasmic side as a synthetic peptide, and its interaction with the -subunit was competed with tetraethylammonium and displayed an affinity in the lower micromolar range. In aequous and physiological salt solution, N-(1-62) showed no well defined three-dimensional structure, it rather existed in a fast equilibrium of multiple weakly structured states. These structural and functional properties of N-(1-62) closely resemble those of the "unstructured" ID from Shaker B, but differ markedly from those of the compactly folded ID of the Kv3.4 -subunit.

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^* This work was supported by Grant Fa332/2-1 from the Deutsche Forschungsgemeinschaft (to B. F. and C. A.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 49-7071-550880; Fax: 49-7071-550890; E-mail: cantz@otogene.de.

^§§ To whom correspondence should be addressed. Tel.: 49-7071-297-7173; Fax: 49-7071-87815; E-mail:bernd.fakler@uni-tuebingen.de.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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