Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside

Abstract

ATP, the principal energy currency of the cell, fuels most biosynthetic reactions in the cytoplasm by its hydrolysis into ADP and inorganic phosphate. Because resynthesis of ATP occurs in the mitochondrial matrix, ATP is exported into the cytoplasm while ADP is imported into the matrix. The exchange is accomplished by a single protein, the ADP/ATP carrier. Here we have solved the bovine carrier structure at a resolution of 2.2 Å by X-ray crystallography in complex with an inhibitor, carboxyatractyloside. Six α-helices form a compact transmembrane domain, which, at the surface towards the space between inner and outer mitochondrial membranes, reveals a deep depression. At its bottom, a hexapeptide carrying the signature of nucleotide carriers (RRRMMM) is located. Our structure, together with earlier biochemical results, suggests that transport substrates bind to the bottom of the cavity and that translocation results from a transient transition from a ‘pit’ to a ‘channel’ conformation.

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Figure 1: Architecture of the ADP/ATP carrier.
Figure 2: Section through the carrier.
Figure 3: The threefold repeat of the ADP/ATP carrier.
Figure 4: Electrostatic potential surface.
Figure 5: The binding of CATR.
Figure 6: The closed conformation of the carrier viewed from the matrix.

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Acknowledgements

We thank the staff at the European Synchrotron Radiation Facilities and of the French beamline BM30A (ESRF) for synchrotron support. We also thank J. P. Rosenbusch and R. Douce for reading the manuscript, and for numerous suggestions and discussions, and P. V. Vignais for helpful comments. This work was supported by the programmes PCV (CNRS) and Emergence (Région Rhône-Alpes) and by the Région Aquitaine.

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Correspondence to Eva Pebay-Peyroula or Gérard Brandolin.

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Pebay-Peyroula, E., Dahout-Gonzalez, C., Kahn, R. et al. Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside. Nature 426, 39–44 (2003). https://doi.org/10.1038/nature02056

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