Abstract
The ubiquitous calcium sensor calmodulin (CaM) mediates two important voltage-gated calcium channel (CaV) calcium-dependent modulatory mechanisms through its interaction with the CaV C-terminal tail. Here, we report the structure of Ca2+/CaM bound to a portion of the CaV1.2 C-terminus with three consecutive CaM binding motifs (A-C-IQ domain). The structure reveals two channel chains dimerized via bridging CaMs and interactions between two long, antiparallel helices. Unlike the crystal structure, the CaM peptide complex is a monomer in solution that corresponds to a single channel chain and two CaMs. Disruption of the crystallographic inter-helix interactions had minimal effect on CDI and CDF of full-length CaV1.2. Moreover, subunit counting experiments using CaV1.2-EGFP fusion proteins clearly indicate that CaV1.2 is a monomer in cell membranes. Thus, contrary to previously proposed models, there appears to be no role for dimerization in channel function.
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