2.A.19.2.7
Ca²⁺/H⁺ antiporter, YfkE (Fujisawa et al., 2009). YfkE is a homotrimer with a subunit size of 451 aas.  The 3-d x-ray strcuture is known to 3.1 Å resolution (Wu et al. 2013).  The conformational transition is triggered by the rotation of the kink angles of transmembrane helices 2 and 7 and is mediated by large conformational changes in their adjacent transmembrane helices 1 and 6.  The inward facing conformation contrasts with the outward facing conformation demonstrated for NCX_Mj (TC# 2.A.19.5.3).  The inward facing conformation has a "hydrophobic seal" that closes the external exit (Wu et al. 2013). Intracellular Ca²⁺ regulation of this H⁺/Ca²⁺ antiporter is mediated by a Ca²⁺ mini-sensor (Lu et al. 2020).  The mini-sensor is formed by six tandem carboxylate residues within the transmembrane (TM)5-6 loop on the intracellular membrane surface. Ca²⁺ binding to the mini-sensor triggers the transition of the transport mode of YfkE from a high-affinity to a low-affinity state. Ca²⁺ binding to the mini-sensor causes an adjacent segment, the exchanger inhibitory peptide (XIP), to move toward the Ca²⁺ translocation pathway to interact with TMS 2a in an inward-open cavity. The specific interaction was demonstrated with a synthetic peptide of the XIP, which inhibits YfkE transport and interrupts conformational changes mediated by the mini-sensor. By comparing the apo and Ca²⁺-bound CAX structures, we propose the following Ca²⁺ transport regulatory mechanism of YfkE: Ca²⁺ binding to the mini-sensor induces allosteric conformational changes in the Ca²⁺ translocation pathway via the XIP, resulting in a rearrangement of the Ca²⁺-binding transport site in the midmembrane. Since the Ca²⁺ mini-sensor and XIP sequences are also identified in other CAX homologs, including the mammalian Na⁺/Ca²⁺ exchanger (NCX), this study provides a regulatory mechanism for the Ca²⁺/cation transporter superfamily (Lu et al. 2020).