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J. Biol. Chem., Vol. 280, Issue 8, 7070-7079, February 25, 2005

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Sites on Calmodulin That Interact with the C-terminal Tail of Ca_v1.2 Channel^*

Liangwen Xiong, Quinn K. Kleerekoper, Rong He, John A. Putkey, and Susan L. Hamilton¶

From the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030 and the Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, Texas 77225

Two fragments of the C-terminal tail of the ₁ subunit (CT1, amino acids 1538–1692 and CT2, amino acids 1596–1692) of human cardiac L-type calcium channel (Ca_V1.2) have been expressed, refolded, and purified. A single Ca²⁺-calmodulin binds to each fragment, and this interaction with Ca²⁺-calmodulin is required for proper folding of the fragment. Ca²⁺-calmodulin, bound to these fragments, is in a more extended conformation than calmodulin bound to a synthetic peptide representing the IQ motif, suggesting that either the conformation of the IQ sequence is different in the context of the longer fragment, or other sequences within CT2 contribute to the binding of calmodulin. NMR amide chemical shift perturbation mapping shows the backbone conformation of calmodulin is nearly identical when bound to CT1 and CT2, suggesting that amino acids 1538–1595 do not contribute to or alter calmodulin binding to amino acids 1596–1692 of Ca_V1.2. The interaction with CT2 produces the greatest changes in the backbone amides of hydrophobic residues in the N-lobe and hydrophilic residues in the C-lobe of calmodulin and has a greater effect on residues located in Ca²⁺ binding loops I and II in the N-lobe relative to loops III and IV in the C-lobe. In conclusion, Ca²⁺-calmodulin assumes a novel conformation when part of a complex with the C-terminal tail of the Ca_V1.2 ₁ subunit that is not duplicated by synthetic peptides corresponding to the putative binding motifs.

Received for publication, September 14, 2004 , and in revised form, December 1, 2004.

^* This work was supported in part by Robert A. Welch Foundation Grant AU-1144 (to J. A. P.), the Muscular Dystrophy Association (to S. L. H.), and National Institutes of Health Grant AR44864 (to S. L. 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 Supplementary Materials.

^¶ To whom correspondence should be addressed: Dept. of Molecular Physiology and Biophysics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030. Tel.: 713-798-3894; Fax: 713-798-5441; E-mail: susanh{at}bcm.tmc.edu.

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