As the prototypical Ca2+ sensor, calmodulin (CaM) is widely expressed in all eukaryotic cells, mediating a variety of cellular signaling processes.A diverse array of target proteins has been identified, such as CaM kinases and ion channels, which interact with CaM.CaM is also a versatile Ca2+ sensor, capable of responding to a wide range of Ca2+ concentrations (10-12 M-10-6 M) in Ca2+-dependent signal transduction.Four canonical EF-hands, with a helix-loop-helix structure, serve as the high affinity Ca2+ binding motifs, with two EF-hands at the N-lobe and the other two at the C-lobe.Upon binding Ca2+, CaM changes its conformation from the closed mode to the open mode, exposing the hydrophobic surfaces within the N-and C-lobes, where interactions with the target proteins take place.Such structural flexibility has been proposed as a mechanism to explain how CaM is able to interact with target proteins which do not seem to share common structural features.CaM, when in complex with the CaM binding domains (CaMBD) from target proteins, is often shown to wrap around CaMBDs with both the N-and C-lobes.So far, most structural studies have focused on how binding of Ca2+ to CaM exposes the hydrophobic surfaces where CaMBD peptides bind.However, very little is known on how binding of CaMBDs can reciprocally affect CaMs conformations and consequently the CaMs affinities for Ca2+.