Structural Basis for the Counter-Transport Mechanism of a H+/Ca2+ Exchanger

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Science  12 Jul 2013:
Vol. 341, Issue 6142, pp. 168-172
DOI: 10.1126/science.1239002

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Inward-Facing Antiporter

Calcium/cation antiporters play a role in regulating the cytosolic calcium concentration by using the electrochemical gradient of other cations to catalyze Ca2+ transport across cell membranes. The structure of a Na+/Ca2+ exchanger in an outward-facing conformation was recently determined. Nishizawa et al. (p. 168, published online 23 May) now report the crystal structure of a H+/Ca2+ exchanger in an inward-facing conformation. Comparison of the structures shows how structural changes create hydrophilic cavities to alternate between the intra- and extracellular sides of the protein, facilitating cation transport.


Ca2+/cation antiporters catalyze the exchange of Ca2+ with various cations across biological membranes to regulate cytosolic calcium levels. The recently reported structure of a prokaryotic Na+/Ca2+ exchanger (NCX_Mj) revealed its overall architecture in an outward-facing state. Here, we report the crystal structure of a H+/Ca2+ exchanger from Archaeoglobus fulgidus (CAX_Af) in the two representatives of the inward-facing conformation at 2.3 Å resolution. The structures suggested Ca2+ or H+ binds to the cation-binding site mutually exclusively. Structural comparison of CAX_Af with NCX_Mj revealed that the first and sixth transmembrane helices alternately create hydrophilic cavities on the intra- and extracellular sides. The structures and functional analyses provide insight into the mechanism of how the inward- to outward-facing state transition is triggered by the Ca2+ and H+ binding.

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