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J. Biol. Chem., Vol. 283, Issue 27, 18937-18946, July 4, 2008

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NMR Analysis of KChIP4a Reveals Structural Basis for Control of Surface Expression of Kv4 Channel Complexes^*

Jochen Schwenk, Gerd Zolles, Nikolaos G. Kandias, Isabel Neubauer, Hubert Kalbacher^¶, Manuel Covarrubias^||, Bernd Fakler, and Detlef Bentrop¹

From the Institute of Physiology II, University of Freiburg, D-79104 Freiburg, Germany, the Department of Pharmacy, School of Health Sciences, University of Patras, GR-26500 Rion, Patras, Greece, the ^¶Interfacultary Institute for Biochemistry, Medical, and Natural Sciences Research Centre, University of Tübingen, D-72074 Tübingen, Germany, and the ^||Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Potassium channel-interacting proteins (KChIPs) are EF-hand calcium-binding proteins of the recoverin/neuronal calcium sensor 1 family that co-assemble with the pore-forming Kv4 -subunits and thus control surface trafficking of the voltage-gated potassium channels mediating the neuronal I_A and cardiac I_to currents. Different from the other KChIPs, KChIP4a largely reduces surface expression of the Kv4 channel complexes. Using solution NMR we show that the unique N terminus of KChIP4a forms a 6-turn -helix that is connected to the highly conserved core of the KChIP protein via a solvent-exposed linker. As identified by chemical shift changes, N-terminal -helix and core domain of KChIP4a interact with each other through the same hydrophobic surface pocket that is involved in intermolecular interaction between the N-terminal helix of Kv4 and KChIP in Kv4-KChIP complexes. Electrophysiological recordings and biochemical interaction assays of complexes formed by wild-type and mutant Kv4 and KChIP4a proteins suggest that competition of these two helical domains for the surface groove is responsible for the reduced trafficking of Kv4-KChIP4a complexes to the plasma membrane. Surface expression of Kv4 complexes may thus be controlled by an auto-inhibitory domain in the KChIP subunit.

Received for publication, February 6, 2008 , and in revised form, April 7, 2008.

Chemical shift assignments have been deposited in the Biological Magnetic Resonance Data Bank (BMRB; http://www.bmrb.wisc.edu) with accession codes 15422 (KChIP4a WT) and 15425 (KChIP4a(1–42)).

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01 NS032337 from NINDS (to M. C.). This work was also supported by grants from the Deutsche Forschungsgemeinschaft (to B. F.) (SFB 388; GRK 843), and the Access to Research Infrastructures activity in the 6th Framework Program of the EC (Contract RII3-026145, EU-NMR). 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 Figs. S1–S4.

¹ To whom correspondence should be addressed: Hermann-Herder-Str. 7, D-79104 Freiburg, Germany. Fax: 49-761-2035191; E-mail: detlef.bentrop{at}physiologie.uni-freiburg.de.

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