2.A.19.3.2
Probable Ca²⁺:3Na⁺ antiporter, Calx (contains two repeat motifs Calx-α and Calxβ, between the two transmembrane domains, as is true of many Ca²⁺:Na⁺ antiporters (Schwarz and Benzer, 1997). CALX activity is inhibited by Ca²⁺ interaction within its two intracellular Ca²⁺ regulatory domains CBD1 and CBD2. The Ca²⁺ inhibition of CALX is achieved by interdomain conformational changes induced by Ca²⁺ binding at CBD1 (Wu et al., 2011). The exchanger is an essential Ca²⁺ extrusion mechanism in excitable cells. It consists of a transmembrane domain and a large intracellular loop that contains the two Ca²⁺-binding domains, CBD1 and CBD2 (de Souza Degenhardt et al. 2021). The two CBDs are adjacent to each other and form a two-domain Ca²⁺ sensor called CBD12. Binding of intracellular Ca²⁺ to CBD12 activates NCX but inhibits the NCX of Drosophila, CALX. CALX and NCX CBD12 constructs display interdomain flexibility in the apo state but assume rigid interdomain arrangements in the Ca²⁺-bound state. CALX-CBD12 preferentially samples closed conformations, whereas the wide-open interdomain arrangement, characteristic of the Ca²⁺-bound state, is less frequently sampled. These results are consistent with the view that Ca²⁺ binding shifts the CBD12 conformational ensemble toward extended conformers, which could be a key step in the NCXs' allosteric regulation mechanism (de Souza Degenhardt et al. 2021).