Structural and dynamic aspects of Ca²⁺ and Mg²⁺ binding of the regulatory domains of the Na⁺/Ca²⁺ exchanger

Intracellular Ca²⁺ regulates the activity of the NCX (Na⁺/Ca²⁺ exchanger) through binding to the cytosolic CBD (Ca²⁺-binding domain) 1 and CBD2. In vitro studies of the structure and dynamics of CBD1 and CBD2, as well as studies of their kinetics and thermodynamics of Ca²⁺ binding, greatly enhanced our understanding of NCX regulation. We describe the fold of the CBDs in relation to other known structures and review Ca²⁺ binding of the different CBD variants from a structural perspective. We also report on new findings concerning Mg²⁺ binding to the CBDs and finally we discuss recent results on CBD1–CBD2 interdomain interactions.