Npgrj_nsmb_1027 1..8

Changes in activity-dependent calcium flux through voltage-gated calcium channels (CaVs) drive two self-regulatory calciumdependent feedback processes that require interaction between Ca2+/calmodulin (Ca2+/CaM) and a CaV channel consensus isoleucine-glutamine (IQ) motif: calcium-dependent inactivation (CDI) and calcium-dependent facilitation (CDF). Here, we report the high-resolution structure of the Ca/CaM–CaV1.2 IQ domain complex. The IQ domain engages hydrophobic pockets in the N-terminal and C-terminal Ca2+/CaM lobes through sets of conserved ‘aromatic anchors.’ Ca2+/N lobe adopts two conformations that suggest inherent conformational plasticity at the Ca2+/N lobe–IQ domain interface. Titration calorimetry experiments reveal competition between the lobes for IQ domain sites. Electrophysiological examination of Ca2+/N lobe aromatic anchors uncovers their role in CaV1.2 CDF. Together, our data suggest that CaV subtype differences in CDI and CDF are tuned by changes in IQ domain anchoring positions and establish a framework for understanding CaM lobe–specific regulation of CaVs.