Structures of CaV2Ca2+/CaM-IQ Domain Complexes Reveal Binding Modes that Underlie Calcium-Dependent Inactivation and Facilitation

Calcium influx drives two opposing voltage-activated calcium channel (Ca-V) self-modulatory processes: calcium-dependent inactivation (CDI) and calcium-dependent facilitation (CDF). Specific Ca2+/calmodulin (Ca2+/CaM) lobes produce CDI and CDF through interactions with the Caval subunit IQ domain. Curiously, Ca2+/CaM lobe modulation polarity appears inverted between Ca(V)1s and Ca(V)2s. Here, we present crystal structures of Ca(V)2.1, Ca(V)2.2, and Ca(V)2.3 Ca2+/CaM-IQ domain complexes. All display binding orientations opposite to Ca(V)1.2 with a physical reversal of the CaM lobe positions relative to the IQ alpha-helix. Titration calorimetry reveals lobe competition for a high-affinity site common to Ca(V)1 and Ca(V)2 IQ domains that is occupied by the CDI lobe in the structures. Electrophysiological experiments demonstrate that the N-terminal Ca(V)2 Ca2+/C-lobe anchors affect CDF. Together, the data unveil the remarkable structural plasticity at the heart of Ca-V feedback modulation and indicate that Ca(V)1 and Ca(V)2 IQ domains bear a dedicated CDF site that exchanges Ca2+/CaM lobe occupants.