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J. Biol. Chem., Vol. 281, Issue 45, 34333-34340, November 10, 2006

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Structure of the Calmodulin II-Spectrin Complex Provides Insight into the Regulation of Cell Plasticity^*

Miljan Simonovic¹, Zhushan Zhang, Carol D. Cianci, Thomas A. Steitz, and Jon S. Morrow²

From the Howard Hughes Medical Institute, Yale University, New Haven, Connecticut 06520 and the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520

II-spectrin is a major cortical cytoskeletal protein contributing to membrane organization and integrity. The Ca²⁺-activated binding of calmodulin to an unstructured insert in the 11th repeat unit of II-spectrin enhances the susceptibility of spectrin to calpain cleavage but abolishes its sensitivity to several caspases and to at least one bacterially derived pathologic protease. Other regulatory inputs including phosphorylation by c-Src also modulate the proteolytic susceptibility of II-spectrin. These pathways, acting through spectrin, appear to control membrane plasticity and integrity in several cell types. To provide a structural basis for understanding these crucial biological events, we have solved the crystal structure of a complex between bovine calmodulin and the calmodulin-binding domain of human II-spectrin (Protein Data Bank ID code 2FOT). The structure revealed that the entire calmodulin-spectrin-binding interface is hydrophobic in nature. The spectrin domain is also unique in folding into an amphiphilic helix once positioned within the calmodulin-binding groove. The structure of this complex provides insight into the mechanisms by which calmodulin, calpain, caspase, and tyrosine phosphorylation act on spectrin to regulate essential cellular processes.

Received for publication, May 12, 2006 , and in revised form, August 21, 2006.

The atomic coordinates and structure factors (code 2FOT) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by National Institutes of Health Grants R01-HL28560 and P01-NS35476 (Ment PI) (to J. S. M.), National Institutes of Health Grant GM22778 (to T. A. S.). 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 A recipient of the Jane Coffin Childs Postdoctoral Fellowship.

² To whom correspondence was addressed: Dept. of Pathology, Yale University School of Medicine, 310 Cedar St. BML 140, New Haven, CT 06520. Tel.: 203-785-3624; Fax: 203-785-7037; E-mail: jon.morrow{at}yale.edu.

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