Proton movement and coupling in the POT family of peptide transporters

POT transporters represent an evolutionarily well-conserved family of proton-coupled transport systems in biology. An unusual feature of the family is their ability to couple the transport of chemically diverse ligands to an inwardly directed proton electrochemical gradient. For example, in mammals,...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2017-12, Vol.114 (50), p.13182-13187
Main Authors: Parker, Joanne L., Li, Chenghan, Brinth, Allete, Wang, Zhi, Vogeley, Lutz, Solcan, Nicolae, Ledderboge-Vucinic, Gregory, Swanson, Jessica M. J., Caffrey, Martin, Voth, Gregory A., Newstead, Simon
Format: Article
Language:English
Subjects:
Bacteria
Bacterial Proteins - chemistry
Bacterial Proteins - metabolism
Binding Sites
Biological Sciences
Cells
Crystal structure
Mammals
Membrane Transport Proteins - chemistry
Membrane Transport Proteins - metabolism
Molecular Dynamics Simulation
Molecules
Peptides
Peptides - metabolism
Protein Binding
Protons
Xanthomonas - chemistry
Xanthomonas - metabolism
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Summary:POT transporters represent an evolutionarily well-conserved family of proton-coupled transport systems in biology. An unusual feature of the family is their ability to couple the transport of chemically diverse ligands to an inwardly directed proton electrochemical gradient. For example, in mammals, fungi, and bacteria they are predominantly peptide transporters, whereas in plants the family has diverged to recognize nitrate, plant defense compounds, and hormones. Although recent structural and biochemical studies have identified conserved sites of proton binding, the mechanism through which transport is coupled to proton movement remains enigmatic. Here we show that different POT transporters operate through distinct proton-coupled mechanisms through changes in the extracellular gate. A high-resolution crystal structure reveals the presence of ordered water molecules within the peptide binding site. Multiscale molecular dynamics simulations confirm proton transport occurs through these waters via Grotthuss shuttling and reveal that proton binding to the extracellular side of the transporter facilitates a reorientation from an inward- to outward-facing state. Together these results demonstrate that within the POT family multiple mechanisms of proton coupling have likely evolved in conjunction with variation of the extracellular gate.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1710727114