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Substrate binding in the mitochondrial ADP/ATP carrier is a step-wise process guiding the structural changes in the transport cycle

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  • Vasiliki Mavridou

    (University of Cambridge, Cambridge Biomedical Campus, Keith Peters Building)

  • Martin S. King

    (University of Cambridge, Cambridge Biomedical Campus, Keith Peters Building)

  • Sotiria Tavoulari

    (University of Cambridge, Cambridge Biomedical Campus, Keith Peters Building)

  • Jonathan J. Ruprecht

    (University of Cambridge, Cambridge Biomedical Campus, Keith Peters Building)

  • Shane M. Palmer

    (University of Cambridge, Cambridge Biomedical Campus, Keith Peters Building)

  • Edmund R. S. Kunji

    (University of Cambridge, Cambridge Biomedical Campus, Keith Peters Building)

Abstract

Mitochondrial ADP/ATP carriers import ADP into the mitochondrial matrix and export ATP to the cytosol to fuel cellular processes. Structures of the inhibited cytoplasmic- and matrix-open states have confirmed an alternating access transport mechanism, but the molecular details of substrate binding remain unresolved. Here, we evaluate the role of the solvent-exposed residues of the translocation pathway in the process of substrate binding. We identify the main binding site, comprising three positively charged and a set of aliphatic and aromatic residues, which bind ADP and ATP in both states. Additionally, there are two pairs of asparagine/arginine residues on opposite sides of this site that are involved in substrate binding in a state-dependent manner. Thus, the substrates are directed through a series of binding poses, inducing the conformational changes of the carrier that lead to their translocation. The properties of this site explain the electrogenic and reversible nature of adenine nucleotide transport.

Suggested Citation

  • Vasiliki Mavridou & Martin S. King & Sotiria Tavoulari & Jonathan J. Ruprecht & Shane M. Palmer & Edmund R. S. Kunji, 2022. "Substrate binding in the mitochondrial ADP/ATP carrier is a step-wise process guiding the structural changes in the transport cycle," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31366-5
    DOI: 10.1038/s41467-022-31366-5
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    References listed on IDEAS

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    1. Eva Pebay-Peyroula & Cécile Dahout-Gonzalez & Richard Kahn & Véronique Trézéguet & Guy J.-M. Lauquin & Gérard Brandolin, 2003. "Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside," Nature, Nature, vol. 426(6962), pages 39-44, November.
    2. Chancievan Thangaratnarajah & Jonathan J. Ruprecht & Edmund R. S. Kunji, 2014. "Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
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    Cited by:

    1. Antoine Gagelin & Corentin Largeau & Sandrine Masscheleyn & Mathilde S. Piel & Daniel Calderón-Mora & Frédéric Bouillaud & Jérôme Hénin & Bruno Miroux, 2023. "Molecular determinants of inhibition of UCP1-mediated respiratory uncoupling," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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