Voltage-dependent calcium channels (CaV) open in response to changes in membrane potential, but their activity is modulated by Ca2+ binding to calmodulin (CaM). Structural studies of this family of channels have focused on CaM bound to the IQ motif; however, the minimal differences between structures cannot adequately describe CaM's role in the regulation of these channels. We report a unique crystal structure of a 77-residue fragment of the CaV1.2 α1 subunit carboxyl terminus, which includes a tandem of the pre-IQ and IQ domains, in complex with Ca2+·CaM in 2 distinct binding modes. The structure of the CaV1.2 fragment is an unusual dimer of 2 coiled-coiled pre-IQ regions bridged by 2 Ca2+·CaMs interacting with the pre-IQ regions and a canonical CaV1-IQ–Ca2+·CaM complex. Native CaV1.2 channels are shown to be a mixture of monomers/dimers and a point mutation in the pre-IQ region predicted to abolish the coiled-coil structure significantly reduces Ca2+-dependent inactivation of heterologously expressed CaV1.2 channels
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