Structural Basis for Ca 2+ Regulation in the Na + /Ca 2+ Exchanger

 Binding of Na + and Ca 2+ ions to the large cytosolic loop of the Na + /Ca 2+ exchanger (NCX) regulates its ion transport across the plasma membrane. We determined the solution structures of two Ca 2+ ‐binding domains (CBD1 and CBD2) that, together with an α‐catenin‐like domain (CLD) form the regulatory exchanger loop. CBD1 and CBD2 constitute a novel Ca 2+ ‐binding motif and are very similar in the Ca 2+ ‐bound state. Strikingly, in the absence of Ca 2+ the upper half of CBD1 unfolds while CBD2 maintains its structural integrity. Together with a sevenfold higher affinity for Ca 2+ this suggests that CBD1 is the primary Ca 2+ sensor. Specific point mutations in either domain largely allow the interchange of their functionality and uncover the mechanism underlying Ca 2+ sensing in NCX.