Structural insight into the ion-exchange mechanism of the sodium/calcium exchanger

Sodium/calcium (Na⁺/Ca²⁺) exchangers (NCX) are membrane transporters that play an essential role in maintaining the homeostasis of cytosolic Ca²⁺ for cell signaling. We demonstrated the Na ⁺/Ca²⁺-exchange function of an NCX from Methanococcus jannaschii (NCX-Mj) and report its 1.9 angstrom crystal structure in an outward-facing conformation. Containing 10 transmembrane helices, the two halves of NCX-Mj share a similar structure with opposite orientation. Four ion-binding sites cluster at the center of the protein: one specific for Ca²⁺ and three that likely bind Na⁺. Two passageways allow for Na ⁺ and Ca²⁺ access to the central ion-binding sites from the extracellular side. Based on the symmetry of NCX-Mj and its ability to catalyze bidirectional ion-exchange reactions, we propose a structure model for the inward-facing NCX-Mj.