Crystal structure of dimeric cardiac L-type calcium channel regulatory domains bridged by Ca2+•calmodulins

Voltage-dependent calcium channels (Ca-v) 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 Ca(v)1.2 alpha(1) subunit carboxyl terminus, which includes a tandem of the pre-IQ and IQ domains, in complex with Ca2+center dot 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 2Ca(2+)center dot CaMs interacting with the pre-IQ regions and a canonical Ca(v)1-IQ-Ca2+center dot CaM complex. Native Ca(v)1.2 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 Ca(v)1.2 channels.