Ca(2+) regulation in the Na(+)/Ca (2+) exchanger features a dual electrostatic switch mechanism.

Ion transport performed by the Na(+)/Ca(2+) exchanger (NCX) is regulated via its cytosolic Ca(2+)-binding domains, CBD1 and CBD2, which act as sensors for intracellular Ca(2+). Striking differences in the electrostatic potential of the Ca(2+)-bound and Ca(2+)-free forms turn the CBD1 and CBD2 Ca(2+)-binding sites into electrostatic switches similar to those of C(2) domains. Binding of Ca(2+) with high affinity to CBD1 induces a conformational change that is relayed to the transmembrane domain and thereby initiates Na(+)/Ca(2+) exchange.

Ca2+ regulation of ion transport in the Na+/Ca2+ exchanger.

The binding of Ca(2+) to two adjacent Ca(2+)-binding domains, CBD1 and CBD2, regulates ion transport in the Na(+)/Ca(2+) exchanger. As sensors for intracellular Ca(2+), the CBDs form electrostatic switches that induce the conformational changes required to initiate and sustain Na(+)/Ca(2+) exchange. Depending on the presence of a few key residues in the Ca(2+)-binding sites, zero to four Ca(2+) ions can bind with affinities between 0.

Ca2+ regulation in the Na+/Ca2+ exchanger features a dual electrostatic switch mechanism.

Regulation of ion-transport in the Na(+)/Ca(2+) exchanger (NCX) occurs via its cytoplasmic Ca(2+)-binding domains, CBD1 and CBD2. Here, we present a mechanism for NCX activation and inactivation based on data obtained using NMR, isothermal titration calorimetry (ITC) and small-angle X-ray scattering (SAXS). We initially determined the structure of the Ca(2+)-free form of CBD2-AD and the structure of CBD2-BD that represent the two major splice variant classes in NCX1.

Structural basis for Ca2+ regulation in the Na+/Ca2+ exchanger.

Binding of Na+ and Ca2+ ions to the large cytosolic loop of the Na+/Ca2+ exchanger (NCX) regulates its ion transport across the plasma membrane. We determined the solution structures of two Ca2+-binding domains (CBD1 and CBD2) that, together with an alpha-catenin-like domain (CLD) form the regulatory exchanger loop. CBD1 and CBD2 constitute a novel Ca2+-binding motif and are very similar in the Ca2+-bound state.

Ca2+ regulation in the Na+/Ca2+ exchanger involves two markedly different Ca2+ sensors.

The plasma membrane Na+/Ca2+ exchanger (NCX) is almost certainly the major Ca2+ extrusion mechanism in cardiac myocytes. Binding of Na+ and Ca2+ ions to its large cytosolic loop regulates ion transport of the exchanger. We determined the solution structures of two Ca2+ binding domains (CBD1 and CBD2) that, together with an alpha-catenin-like domain (CLD), form the regulatory exchanger loop.