Structural Basis for Calmodulin as a Dynamic Calcium Sensor

Calmodulin is a prototypical and versatile Ca2+ sensor with EF hands as its high-affinity Ca2+ binding domains. Calmodulin is present in all eukaryotic cells, mediating Ca2+-dependent signaling. Upon binding Ca2+, calmodulin changes its conformation to form complexes with a diverse array of target proteins. Despite a wealth of knowledge on calmodulin, little is known on how target proteins regulate calmodulin's ability to bind Ca2+. Here, we take advantage of two splice variants of SK2 channels, which are activated by Ca2+-bound calmodulin but show different sensitivity to Ca2+ for their activation. Protein crystal structures and other experiments show that, depending on which SK2 splice variant it binds to, calmodulin adopts drastically different conformations with different affinities for Ca2+ at its C-lobe. Such target protein-induced conformational changes make calmodulin a dynamic Ca2+ sensor capable of responding to different Ca2+ concentrations in cellular Ca2+ signaling. ► We show structure of CaM-CaMBD2-b, a SK2 splice variant with reduced Ca2+ sensitivity ► Dramatic changes in the CaM structure in CaM-CaMBD2-b compared to CaM in CaM-CaMBD2-a ► Conformational changes at the CaM C-lobe result in its reduced affinity for Ca2+ ► Results demonstrate CaM alters its affinity for Ca2+ induced by the target proteins