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Na + /Ca 2+  exchanger (NCX) proteins extrude Ca 2+  from the cell to maintain cellular homeostasis. Since NCX proteins contribute to numerous physiological and pathophysiological events, their pharmacological targeting has been desired for a long time. This intervention remains challenging owing to our poor understanding of the underlying structure-dynamic mechanisms. Recent structural studies have shed light on the structure-function relationships underlying the ion-transport and allosteric regulation of NCX. The crystal structure of an archaeal NCX (NCX_Mj) along with molecular dynamics simulations and ion flux analyses, have assigned the ion binding sites for 3Na +  and 1Ca 2+ , which are being transported in separate steps. In contrast with NCX_Mj, eukaryotic NCXs contain the regulatory Ca 2+ -binding domains, CBD1 and CBD2, which affect the membrane embedded ion-transport domains over a distance of ~80 Å. The Ca 2+ -dependent regulation is ortholog, isoform, and splice-variant dependent to meet physiological requirements, exhibiting either a positive, negative, or no response to regulatory Ca 2+ . The crystal structures of the two-domain (CBD12) tandem have revealed a common mechanism involving a Ca 2+ -driven tethering of CBDs in diverse NCX variants. However, dissociation kinetics of occluded Ca 2+  (entrapped at the two-domain interface) depends on the alternative-splicing segment (at CBD2), thereby representing splicing-dependent dynamic coupling of CBDs. The HDX-MS, SAXS, NMR, FRET, equilibrium  45 Ca 2+  binding and stopped-flow techniques provided insights into the dynamic mechanisms of CBDs. Ca 2+  binding to CBD1 results in a population shift, where more constraint conformational states become highly populated without global conformational changes in the alignment of CBDs. This mechanism is common among NCXs. Recent HDX-MS studies have demonstrated that the apo CBD1 and CBD2 are stabilized by interacting with each other, while Ca 2+  binding to CBD1 rigidifies local backbone segments of CBD2, but not of CBD1. The extent and strength of Ca 2+ -dependent rigidification at CBD2 is splice-variant dependent, showing clear correlations with phenotypes of matching NCX variants. Therefore, diverse NCX variants share a common mechanism for the initial decoding of the regulatory signal upon Ca 2+  binding at the interface of CBDs, whereas the allosteric message is shaped by CBD2, the dynamic features of which are dictated by the splicing segment.

Structural Features of Ion Transport and Allosteric Regulation in Sodium-Calcium Exchanger (NCX) Proteins