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.