A crucial event in calcium signaling is the transition of a calcium sensor from the apo (Ca(2+) free) to the holo (Ca(2+)-saturated) state. Caldendrin (CDD) is a neuronal Ca(2+)-binding protein with two functional (EF3 and EF4) and two atypical (EF1 and EF2), non-Ca(2+)-binding EF-hand motifs. During the transition from the apo to the holo state, guided by the stepwise filling of Ca(2+), the protein passes through distinct states and acquires a stable conformational state when only EF3 is occupied by Ca(2+). This state is characterized by a Ca(2+)-derived structural gain in EF3 with destabilization of the EF4 motif. At higher Ca(2+) levels, when Ca(2+) fills in EF4, the motif regains stability. EF3 controls initial Ca(2+) binding and dictates structural destabilization of EF4. It is likely that this unexpected intermotif communication will have an impact on Ca(2+)-dependent target interactions.
