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

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  • Andrew B Waight, Department of Biochemistry and Biophysics, University of California, San Francisco, Danmark
  • Bjørn Panyella Pedersen
  • Avner Schlessinger, Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, University of California, San Francisco, California 94158, USA, USA
  • Massimiliano Bonomi, Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, University of California, San Francisco, California 94158, USA, USA
  • Bryant H Chau, Department of Biochemistry and Biophysics, University of California, San Francisco, USA
  • Zygy Roe-Zurz, Department of Biochemistry and Biophysics, University of California, San Francisco, USA
  • Aaron J Risenmay, Department of Biochemistry and Biophysics, University of California, San Francisco, USA
  • Andrej Sali, Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, University of California, San Francisco, California 94158, USA, USA
  • Robert M Stroud, Department of Biochemistry and Biophysics, University of California, San Francisco, USA

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.

OriginalsprogEngelsk
TidsskriftNature
Vol/bind499
Nummer7456
Sider (fra-til)107-110
Antal sider4
ISSN0028-0836
DOI
StatusUdgivet - 4 jul. 2013

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