Proton-Coupled Peptide Transport Mechanisms

Proton-coupled peptide transporters form a widespread class of secondary active carriers that harness the inwardly directed proton electrochemical gradient to import di- and tripeptides across cellular membranes. Members of this family share a conserved major facilitator superfamily (MFS) fold comprising twelve transmembrane helices, arranged as two pseudo-symmetrical six-helix bundles. Transport proceeds via an alternating-access cycle in which proton binding induces conformational changes that open and close gates on opposite sides of the membrane, allowing peptide substrates to bind on the extracellular face and be released into the cytosol. These transporters are essential for nutrient uptake in bacteria, dietary peptide absorption in the intestine, peptide reabsorption in the kidney and lysosomal recycling of proteolytic fragments. Their broad substrate promiscuity underpins roles in drug pharmacokinetics, as numerous peptidomimetic therapeutics exploit peptide carriers to enhance oral bioavailability and tissue targeting. Recent structural and functional studies have elucidated the molecular basis of substrate recognition, proton–peptide coupling and gating dynamics, paving the way for rational modulation of transporter activity in health and disease.

Research from Nature Portfolio

Recent studies have resolved the structure of a peptide/histidine transporter in an outward-open conformation and revealed how its N-terminal adaptor folds into the central cavity of the inward-open state, shedding light on the molecular basis of receptor-mediated signalling in innate immunity. This work highlights the dual role of the transporter both as a substrate carrier and as a recruitment platform for an interferon-activating adaptor, with implications for autoimmune disease therapeutics. In parallel, the deorphanisation of a lysosomal dipeptide transporter complexed with a glycosylated accessory subunit has defined its uniporter mechanism: cryo-electron microscopy structures and molecular dynamics reveal how the heterodimer selects cationic, neutral and anionic dipeptides, providing an alternative route for recycling proteolysis products when conventional amino acid exporters are saturated.

Proton-Coupled Peptide Transport Mechanisms publication trend

The graph below shows the total number of articles in proton-coupled peptide transport mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Proton electrochemical gradient: The combined difference in proton concentration and electrical charge across a membrane that provides the driving force for secondary active transport.

Major facilitator superfamily (MFS): A large group of membrane transport proteins characterised by a common fold of twelve transmembrane helices arranged in two six-helix bundles.

Alternating-access mechanism: A transport model in which conformational changes alternately expose the substrate-binding site to either side of the membrane, preventing a continuous channel.

Uniporter: A membrane transporter that facilitates passive movement of one substrate species down its concentration gradient, here referring to dipeptide export driven by existing gradients.

References

1. Molecular basis of TASL recruitment by the peptide/histidine transporter 1, PHT1. Nature Communications (2023).
2. MFSD1 with its accessory subunit GLMP functions as a general dipeptide uniporter in lysosomes. Nature Cell Biology (2024).
3. The mechanism of mammalian proton-coupled peptide transporters. eLife (2024).
4. Plasticity of the binding pocket in peptide transporters underpins promiscuous substrate recognition. Cell Reports (2023).
5. Molecular Insights to the Structure-Interaction Relationships of Human Proton-Coupled Oligopeptide Transporters (PepTs). Pharmaceutics (2023).