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J. Biol. Chem., Vol. 280, Issue 45, 37941-37947, November 11, 2005

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Localization of a Disease-associated Mutation Site in the Three-dimensional Structure of the Cardiac Muscle Ryanodine Receptor^*

Zheng Liu1, Ruiwu Wang, Jing Zhang, S. R. Wayne Chen, and Terence Wagenknecht¶

From the Wadsworth Center, New York State Department of Health, Albany, New York 12201, the Departments of Physiology and Biophysics and of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta T2N 4N1, Canada, and the ^¶Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, New York 12201

The cardiac muscle ryanodine receptor (RyR2) functions as a calcium release channel in the heart. Up to 40 mutations in RyR2 have been linked to genetic forms of sudden cardiac death. These mutations are largely clustered in three regions of the sequence of the polypeptide: one near the N terminus, one in the central region, and the third in the C-terminal region. The central region includes 11 mutations, and an isoleucine-proline motif (positions 2427 and 2428) in the same region is predicted to contribute to the binding of FKBP12.6 protein. We have mapped the central mutation site in the three-dimensional structure of RyR2 by green fluorescent protein insertion, cryoelectron microscopy, and single-particle image processing. The central mutation site was mapped to a "bridge" of density that connects cytoplasmic domains 5 and 6, which have been suggested to undergo conformational changes during channel gating. Moreover, the location of this central mutation site is not close to that of the FKBP12.6-binding site mapped previously by cryoelectron microscopy.

Received for publication, May 25, 2005 , and in revised form, August 22, 2005.

^* This work was supported by American Heart Association Grant 0430076N (to Z. L.), by National Institutes of Health Grant AR40615 (to T. W.), and by research grants from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada, Alberta (to S. R. W. C.). The work performed in the Resource for Visualization of Biological Complexity of the Wadsworth Center was supported by National Institutes of Health Biotechnological Resource Grant RR01219. 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.

¹ To whom correspondence should be addressed: Wadsworth Center, New York State Dept. of Health, Empire State Plaza, Albany, NY 12201. Tel.: 518-474-6516; Fax: 518-474-7992; E-mail: liuz{at}wadsworth.org.

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