Structural basis for alternating access of a eukaryotic calcium/proton exchanger

Andrew B. Waight, Bjørn Panyella Pedersen, Avner Schlessinger, Massimiliano Bonomi, Bryant H. Chau, Zygy Roe-Zurz, Aaron J. Risenmay, Andrej Sali, Robert M. Stroud

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

Eukaryotic Ca 2+ regulation involves sequestration into intracellular organelles, and expeditious Ca 2+ release into the cytosol is a hallmark of key signalling transduction pathways. Bulk removal of Ca 2+ after such signalling events is accomplished by members of the Ca 2+:cation (CaCA) superfamily. 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 responsible for the re-establishment of Ca 2+ resting potential in muscle cells, neuronal signalling and Ca 2+ reabsorption in the kidney. 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. The cytosol-facing conformations within the CaCA superfamily are unknown, and the transport mechanism remains speculative. Here we determine a crystal structure of the Saccharomyces cerevisiae vacuolar Ca 2+/H + exchanger (Vcx1) at 2.3 Å resolution in a cytosol-facing, substrate-bound conformation. Vcx1 is the first structure, to our knowledge, 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 by which the CaCA superfamily performs high-throughput Ca 2+ transport across membranes.

Original languageEnglish
Pages (from-to)107-110
Number of pages4
JournalNature
Volume499
Issue number7456
DOIs
StatePublished - 2013
Externally publishedYes

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