SLC15A5

Model summary

A human multi-pass membrane transporter that uses the proton gradient to move di- and tripeptides across biological membranes. It concentrates oligopeptide flux from the acidic lysosomal lumen to the cytosol and can also mediate peptide uptake at the cell surface. The transporter’s fold and proton-coupled mechanism enable alternating-access translocation, integrating lysosomal peptide salvage with broader cellular peptide import and ion-gradient–dependent transport pathways.

Predicted Gene Ontology terms

1. 01

   I begin with the InterPro architecture.

   The sequence is dominated by IPR036259 (MFS transporter superfamily, residues 16–537), a hallmark of 12-helix secondary-active carriers that shuttle small solutes across membranes via alternating-access conformational changes. Nested within this scaffold is IPR000109 (Proton-dependent oligopeptide transporter family, residues 114–492), which specifies the substrate class and coupling mechanism: this family forms the heterodimeric POT/PTR system that uses the proton gradient to drive uptake of di- and tripeptides. The ordered layout—an MFS core spanning nearly the full length with a POT-family-defining internal region—dictates a multi-pass transporter that binds and translocates oligopeptides through proton-coupled cycles.

2. 02

   This architecture causes a molecular function centered on transmembrane solute transport.

   The POT/PTR signature (IPR000109) narrows the chemistry to proton-coupled oligopeptide translocation, while the extensive MFS fold provides the alternating-access mechanism and the hydrophobic conduit for substrate passage. Such transporters typically present broad interaction surfaces for assembly and regulation, supporting GO:0005515 protein binding as an intrinsic property of their function and trafficking.

3. 03

   From this molecular function, the biological processes follow.

   Proton-coupled oligopeptide movement across membranes directly instantiates GO:0035672 oligopeptide transmembrane transport and GO:0042938 dipeptide transport. Because the transporter harnesses the proton motive force to drive solute flux, it participates in GO:0006811 monoatomic ion transport via the coupled H+ pathway that energizes peptide uptake. When positioned at the cell surface, its vectorial uptake corresponds to GO:0098739 import across plasma membrane.

4. 04

   Cellular localization is dictated by both the transporter’s energy coupling and its trafficking itinerary.

   The MFS/POT framework and proton-gradient dependence align with acidic compartments, and experimental and predictive evidence converge on a lysosomal membrane residence. This matches GO:0005765 lysosomal membrane and explains why the transporter concentrates luminal oligopeptides generated by endolysosomal proteolysis into the cytosol. The multi-pass nature and endomembrane itinerary are consistent with a lysosome-enriched distribution while allowing transient presence at the plasma membrane during biosynthetic delivery and retrieval.

5. 05

   Mechanistically, the transporter likely operates as a proton-driven alternating-access carrier that cycles between outward- and inward-facing states to move di- and tripeptides.

   In the lysosome, the acidic lumen supplies both substrate (generated by cathepsins) and the energy gradient that biases transport. I hypothesize that it forms or joins larger assemblies: a POT/PTR heterodimer and accessory complexes that couple to endolysosomal trafficking. Candidate partners include another POT-family subunit that stabilizes the heterodimer, lysosomal membrane scaffolds that organize the endomembrane system, and proton-gradient generators that tune its activity. Together, these interactions would coordinate oligopeptide salvage from the lysosome to cytosolic pools and occasional uptake at the cell surface.