High-pH structure of EmrE reveals the mechanism of proton-coupled substrate transport

Alexander A. Shcherbakov, Peyton J. Spreacker, Aurelio J. Dregni, Katherine A. Henzler-Wildman and Mei Hong ()
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Alexander A. Shcherbakov: Massachusetts Institute of Technology
Peyton J. Spreacker: University of Wisconsin at Madison
Aurelio J. Dregni: Massachusetts Institute of Technology
Katherine A. Henzler-Wildman: University of Wisconsin at Madison
Mei Hong: Massachusetts Institute of Technology

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract The homo-dimeric bacterial membrane protein EmrE effluxes polyaromatic cationic substrates in a proton-coupled manner to cause multidrug resistance. We recently determined the structure of substrate-bound EmrE in phospholipid bilayers by measuring hundreds of protein-ligand HN–F distances for a fluorinated substrate, 4-fluoro-tetraphenylphosphonium (F4-TPP+), using solid-state NMR. This structure was solved at low pH where one of the two proton-binding Glu14 residues is protonated. Here, to understand how substrate transport depends on pH, we determine the structure of the EmrE-TPP complex at high pH, where both Glu14 residues are deprotonated. The high-pH complex exhibits an elongated and hydrated binding pocket in which the substrate is similarly exposed to the two sides of the membrane. In contrast, the low-pH complex asymmetrically exposes the substrate to one side of the membrane. These pH-dependent EmrE conformations provide detailed insights into the alternating-access model, and suggest that the high-pH conformation may facilitate proton binding in the presence of the substrate, thus accelerating the conformational change of EmrE to export the substrate.

Date: 2022
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DOI: 10.1038/s41467-022-28556-6

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