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J. Biol. Chem., Vol. 283, Issue 9, 5815-5830, February 29, 2008

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The KCNQ1 (Kv7.1) COOH Terminus, a Multitiered Scaffold for Subunit Assembly and Protein Interaction^*

Reuven Wiener¹, Yoni Haitin, Liora Shamgar, M. Carmen Fernández-Alonso^¶, Ariadna Martos, Orna Chomsky-Hecht, Germán Rivas^¶, Bernard Attali, and Joel A. Hirsch²

From the Department of Biochemistry, The Daniella Rich Institute for Structural Biology, Faculty of Life Sciences, and the Department of Physiology and Pharmacology, Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel and ^¶CIB-Consejo Superior de Investigaciones Científicas, E-28040 Madrid, Spain

The Kv7 subfamily of voltage-dependent potassium channels, distinct from other subfamilies by dint of its large intracellular COOH terminus, acts to regulate excitability in cardiac and neuronal tissues. KCNQ1 (Kv7.1), the founding subfamily member, encodes a channel subunit directly implicated in genetic disorders, such as the long QT syndrome, a cardiac pathology responsible for arrhythmias. We have used a recombinant protein preparation of the COOH terminus to probe the structure and function of this domain and its individual modules. The COOH-terminal proximal half associates with one calmodulin constitutively bound to each subunit where calmodulin is critical for proper folding of the whole intracellular domain. The distal half directs tetramerization, employing tandem coiled-coils. The first coiled-coil complex is dimeric and undergoes concentration-dependent self-association to form a dimer of dimers. The outer coiled-coil is parallel tetrameric, the details of which have been elucidated based on 2.0Å crystallographic data. Both coiled-coils act in a coordinate fashion to mediate the formation and stabilization of the tetrameric distal half. Functional studies, including characterization of structure-based and long QT mutants, prove the requirement for both modules and point to complex roles for these modules, including folding, assembly, trafficking, and regulation.

Received for publication, April 6, 2007 , and in revised form, September 10, 2007.

The atomic coordinates and structure factors (code 3BJ4) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work is supported in part by Israel Science Foundation Grant 672/05 and Wolfson Family funds (to B. A.) and by Israel Science Foundation Grant 1201/04 (to J. A. H.). 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 Table 1 and Figs. 1 and 2.

¹ Supported in part by a matching Tel Aviv University Rector doctoral fellowship.

² To whom correspondence should be addressed: Dept. of Biochemistry, Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel. Tel.: 972-3-640-6211; Fax: 972-3-640-7931; E-mail: jhirsch{at}post.tau.ac.il.

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