Probing the Interactions of Carboxy-atractyloside and Atractyloside with the Yeast Mitochondrial ADP/ATP Carrier

SummaryMitochondrial ADP/ATP carriers are inhibited by two natural compounds, atractyloside (ATR) or carboxy-atractyloside (CATR), which differ by one carboxylate group. The interactions of the inhibitors with the carrier were investigated by single-molecule force spectroscopy. Transmembrane α helices of the ATR-inhibited carrier displayed heterogeneous mechanical and kinetic properties. Whereas α helix H2 showed the most brittle mechanical properties and lowest kinetic stability, α helix H5 was mechanically the most flexible and possessed a kinetic stability 9 orders of magnitude greater than that of α helix H2. In contrast, CATR-binding substantially increased the kinetic stability of α helix H2 and tuned the mechanical flexibility of α helices H5 and H6. NMR spectroscopy confirmed that the additional carboxylate group of CATR binds to the sixth α helix, indicating that the enhanced stability of H2 is mediated via interactions between CATR and H6.

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