Intermotif Communication Induces Hierarchical Ca²⁺ Filling of Caldendrin

A crucial event in calcium signaling is the transition of a calcium sensor from the apo (Ca²⁺ free) to the holo (Ca²⁺-saturated) state. Caldendrin (CDD) is a neuronal Ca²⁺-binding protein with two functional (EF3 and EF4) and two atypical (EF1 and EF2), non-Ca²⁺-binding EF-hand motifs. During the transition from the apo to the holo state, guided by the stepwise filling of Ca²⁺, the protein passes through distinct states and acquires a stable conformational state when only EF3 is occupied by Ca²⁺. This state is characterized by a Ca²⁺-derived structural gain in EF3 with destabilization of the EF4 motif. At higher Ca²⁺ levels, when Ca²⁺ fills in EF4, the motif regains stability. EF3 controls initial Ca²⁺ binding and dictates structural destabilization of EF4. It is likely that this unexpected intermotif communication will have an impact on Ca²⁺-dependent target interactions.