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

Vasiliki Mavridou, Martin S King, Sotiria Tavoulari, Jonathan J Ruprecht, Shane M Palmer, Edmund R S Kunji

Nature communications 2022 Jun 23

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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. © 2022. The Author(s).

Citation

Vasiliki Mavridou, Martin S King, Sotiria Tavoulari, Jonathan J Ruprecht, Shane M Palmer, Edmund R S Kunji. Substrate binding in the mitochondrial ADP/ATP carrier is a step-wise process guiding the structural changes in the transport cycle. Nature communications. 2022 Jun 23;13(1):3585