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The structures of the peptide transporters SLC15A3 and SLC15A4 reveal the recognition mechanisms for substrate and TASL. | LitMetric
The solute carrier family 15 members 3 and 4 (SLC15A3 and SLC15A4) are closely related endolysosomal peptide transporters that transport free histidine and certain dipeptides from the lumen to cytosol. Besides, SLC15A4 also functions as a scaffold protein for the recruitment of the adapter TASL for interferon regulatory factor 5 (IRF5) activation downstream of innate immune TLR7-9 signaling. However, the molecular basis for the substrate recognition and TASL recruitment by these membrane proteins is not well understood. Here, we report the cryoelectron microscopy (cryo-EM) structure of apo SLC15A3 and structures of SLC15A4 in the absence or presence of the substrate, revealing the specific dipeptide recognition mechanism. Each SLC15A3 and SLC15A4 protomer adopts an outward-facing conformation. Furthermore, we also present the cryo-EM structure of a SLC15A4-TASL complex. The N terminal region of TASL forms a helical structure that inserts deeply into the inward-facing cavity of SLC15A4.
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