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J. Biol. Chem., Vol. 281, Issue 31, 21577-21581, August 4, 2006

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The Crystal Structure of the Primary Ca²⁺ Sensor of the Na⁺/Ca²⁺ Exchanger Reveals a Novel Ca²⁺ Binding Motif^*

Debora A. Nicoll, Michael R. Sawaya, Seunghyug Kwon, Duilio Cascio, Kenneth D. Philipson, and Jeff Abramson¹

From the Department of Physiology and the Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, California 90095 and the Department of Chemistry and Biochemistry, UCLA-Department of Energy Center for Genomics and Proteomics, Molecular Biology Institute, University of California, Los Angeles, California 90095

The Na⁺/Ca²⁺ exchanger is a plasma membrane protein that regulates intracellular Ca²⁺ levels in cardiac myocytes. Transport activity is governed by Ca²⁺, and the primary Ca²⁺ sensor (CBD1) is located in a large cytoplasmic loop connecting two transmembrane helices. The binding of Ca²⁺ to the CBD1 sensory domain results in conformational changes that stimulate the exchanger to extrude Ca²⁺. Here, we present a crystal structure of CBD1 at 2.5Å resolution, which reveals a novel Ca²⁺ binding site consisting of four Ca²⁺ ions arranged in a tight planar cluster. This intricate coordination pattern for a Ca²⁺ binding cluster is indicative of a highly sensitive Ca²⁺ sensor and may represent a general platform for Ca²⁺ sensing.

Received for publication, May 15, 2006

^* This work was supported by National Institutes of Health Grant HL-49101 (to K. D. P.) and American Heart Association Grant 0630258N (to J. A.). 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 Tables 1 and 2. The atomic coordinates and structure factors (code 2DPK) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

¹ To whom correspondence should be addressed: Dept. of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095. Tel.: 310-825-3913; Fax: 310-206-5661; E-mail: jabramson{at}mednet.ucla.edu.

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