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A Ca²⁺-Binding Domain in RyR1 that Interacts with the Calmodulin Binding Site and Modulates Channel Activity

Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas

Correspondence: Address reprint requests to Susan L. Hamilton, 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.

A fragment of RyR1 (amino acids 4064–4210) is predicted to fold to at least one lobe of calmodulin and to bind Ca²⁺. This fragment of RyR1 (R4064–4210) was subcloned, expressed, refolded, and purified. Consistent with the predicted folding pattern, R4064–4210 was found to bind two molecules of Ca²⁺ and undergo a structural change upon binding Ca²⁺ that exposes hydrophobic amino acids. R4064–4210 also binds to RyR1, the L-type Ca²⁺ channel (Cav_1.1), and several synthetic calmodulin binding peptides. Both R4064–4210 and a peptide representing the calmodulin-binding region of RyR1 (R3614–3643) alter the Ca²⁺ dependence of (³H)ryanodine binding to RyR1, suggesting that they may both be interfering with an intramolecular interaction between amino acids 4064–4210 and amino acids 3614–3643 in the native RyR1 to alter or regulate the response of the channel to changes in Ca²⁺ concentration. The finding that a domain within RyR1 binds Ca²⁺ and interacts with calmodulin-binding motifs may provide insights into the mechanism for calcium- and calmodulin-dependent regulation of this channel and perhaps for its regulation by the L-type Ca²⁺ channel.

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