Rethinking the Bounds of Ion-Coupled Transport

Abstract

Ion-coupled transporters are involved in numerous physiological processes, including nutrient acquisition, ion homeostasis, and toxin excretion, but the mechanistic details of how the energy stored in ion gradients is translated to uphill substrate transport are still poorly understood. This puzzle is especially interesting in the case of multidrug transporters, which must be able to couple ion flux to the transport of chemically diverse substrates. Using nuclear magnetic resonance (NMR) spectroscopy, our lab discovered that the proton-coupled multidrug transporter EmrE from E. coli must be capable of coupling drug and proton with multiple different stoichiometries. Here, we use mass action kinetic simulations and solid supported membrane (SSM) electrophysiology to rethink the bounds of ion-coupled transport. These results suggest the intriguing possibility that it may be possible to reverse the direction of driven transport, hijacking promiscuous transporters for targeted drug delivery. Our work has broad implications for the mechanism, evolution, and design of ion-coupled transporters.