Eukaryotic Ca 2+ regulation involves sequestration into intracellular organelles, and expeditious Ca 2+ release into the cytosol is a hallmark of key signaling transduction pathways. Bulk removal of Ca 2+ following such signaling events is accomplished by members of the Ca 2+ :cation (CaCA) superfamily [1] [2] [3] [4] [5] . The CaCA superfamily includes the Na + /Ca 2+ (NCX) and Ca 2+ /H + (CAX) antiporters, and in mammals the NCX and related proteins constitute families SLC8 and SLC24, and are

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... responsible for the re-establishment of Ca 2+ resting potential in muscle cells, neuronal signaling and Ca 2+ reabsorption in the kidney 1, 6 . The CAX family members maintain cytosolic Ca 2+ homeostasis in plants and fungi during steep rises in intracellular Ca 2+ due to environmental changes, or following signal transduction caused by events such as hyperosmotic shock, hormone response and response to mating pheromones [7] [8] [9] [10] [11] [12] [13] . The cytosol-facing conformations within the CaCA superfamily are unknown, and the transport mechanism remains speculative. We determined a crystal structure of the Saccharomyces cerevisiae vacuolar Ca 2+/ H + exchanger (VCX1) at 2.3Å resolution in a cytosol-facing, substrate bound conformation. VCX1 is the first structure within the CAX family, and it describes the key cytosol-facing conformation of the CaCA superfamily, providing the structural basis for a novel alternating access mechanism Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms