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Apocalmodulin and Ca²⁺Calmodulin-Binding Sites on the Ca_V1.2 Channel

Wei Tang ^*, D. Brent Halling ^*, D. J. Black , Patricia Pate ^*, Jia-Zheng Zhang ^*, Steen Pedersen ^*, Ruth A. Altschuld  and Susan L. Hamilton ^*

^* Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas; and Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio

Correspondence: Address reprint requests to Susan L. Hamilton, Dept. of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston TX 77030. Tel.: 713-798-3894; Fax: 713-798-5441; E-mail: susanh{at}bcm.tmc.edu.

The cardiac L-type voltage-dependent calcium channel is responsible for initiating excitation-contraction coupling. Three sequences (amino acids 1609–1628, 1627–1652, and 1665–1685, designated A, C, and IQ, respectively) of its ₁ subunit contribute to calmodulin (CaM) binding and Ca²⁺-dependent inactivation. Peptides matching the A, C, and IQ sequences all bind Ca²⁺CaM. Longer peptides representing A plus C (A-C) or C plus IQ (C-IQ) bind only a single molecule of Ca²⁺CaM. Apocalmodulin (ApoCaM) binds with low affinity to the IQ peptide and with higher affinity to the C-IQ peptide. Binding to the IQ and C peptides increases the Ca²⁺ affinity of the C-lobe of CaM, but only the IQ peptide alters the Ca²⁺ affinity of the N-lobe. Conversion of the isoleucine and glutamine residues of the IQ motif to alanines in the channel destroys inactivation (Zühlke et al., 2000). The double mutation in the peptide reduces the interaction with apoCaM. A mutant CaM unable to bind Ca²⁺ at sites 3 and 4 (which abolishes the ability of CaM to inactivate the channel) binds to the IQ, but not to the C or A peptide. Our data are consistent with a model in which apoCaM binding to the region around the IQ motif is necessary for the rapid binding of Ca²⁺ to the C-lobe of CaM. Upon Ca²⁺ binding, this lobe is likely to engage the A-C region.

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