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Intracellular Ca2+ regulation of H+/Ca2+ antiporter YfkE mediated by a Ca2+ mini-sensor

Shuo Lu,Zhenlong Li,A. Gorfe,Lei Zheng

Published 2020 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Ca2+ is essential for life, not only as a basic element, but also due to its versatile role in cellular signaling. H+/Ca2+ antiporter CAX proteins facilitate cellular Ca2+ homeostasis in microorganisms, yeast, and plants by catalyzing Ca2+ extrusion from the cytosol driven by an inward H+ gradient. In this paper, we reveal a self-regulatory mechanism of CAX. We found that CAX senses changes in cytosolic Ca2+ levels to adjust its Ca2+ transport activity. This regulation is mediated by a Ca2+ mini-sensor to alter the conformation of the Ca2+ translocation pathway. This regulatory mechanism is conserved in both prokaryotes and eukaryotes. Our study provides insights into the working mechanism of these important Ca2+ transporter proteins in the cell membrane. The H+/Ca2+ (calcium ion) antiporter (CAX) plays an important role in maintaining cellular Ca2+ homeostasis in bacteria, yeast, and plants by promoting Ca2+ efflux across the cell membranes. However, how CAX facilitates Ca2+ balance in response to dynamic cytosolic Ca2+ perturbations is unknown. Here, we identified a type of Ca2+ “mini-sensor” in YfkE, a bacterial CAX homolog from Bacillus subtilis. 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. Molecular dynamics simulation and fluorescence resonance energy transfer analysis suggest that Ca2+ binding to the mini-sensor causes an adjacent segment, namely, the exchanger inhibitory peptide (XIP), to move toward the Ca2+ translocation pathway to interact with TM2a 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 and/or Ca2+ transporters, including the mammalian Na+/Ca2+ exchanger (NCX), our study provides a regulatory mechanism for the Ca2+/cation transporter superfamily.

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