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Start Over Author "Hamilton, Susan" Journal biophysical journal
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14. Apocalmodulin and Ca2+ calmodulin-binding sites on the CaV1.2 channel.

Author

Tang W, Halling DB, Black DJ, Pate P, Zhang JZ, Pedersen S, Altschuld RA, and Hamilton SL

Subjects
Alanine chemistry, Animals, Binding Sites, Calcium metabolism, Calcium Channels, L-Type metabolism, Calmodulin genetics, Cattle, Dose-Response Relationship, Drug, Electrophoresis, Gel, Two-Dimensional, Electrophoresis, Polyacrylamide Gel, Glutamine chemistry, Isoleucine chemistry, Mutation, Peptides chemistry, Protein Binding, Protein Structure, Tertiary, Spectrometry, Fluorescence, Calcium chemistry, Calcium Channels, L-Type chemistry, Calmodulin chemistry
Abstract

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 alpha(1) subunit contribute to calmodulin (CaM) binding and Ca(2+)-dependent inactivation. Peptides matching the A, C, and IQ sequences all bind Ca(2+)CaM. Longer peptides representing A plus C (A-C) or C plus IQ (C-IQ) bind only a single molecule of Ca(2+)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 Ca(2+) affinity of the C-lobe of CaM, but only the IQ peptide alters the Ca(2+) 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 Ca(2+) 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 Ca(2+) to the C-lobe of CaM. Upon Ca(2+) binding, this lobe is likely to engage the A-C region.

Published
2003
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