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TitleThe structures of the peptide transporters SLC15A3 and SLC15A4 reveal the recognition mechanisms for substrate and TASL.
Journal, issue, pagesStructure, Vol. 33, Issue 2, Page 330-337.e4, Year 2025
Publish dateFeb 6, 2025
AuthorsZhikuan Zhang / Shota Kasai / Kentaro Sakaniwa / Akiko Fujimura / Umeharu Ohto / Toshiyuki Shimizu /
PubMed AbstractThe 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 ...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.
External linksStructure / PubMed:39719710
MethodsEM (single particle)
Resolution2.83 - 3.91 Å
Structure data

EMDB-37897, PDB-8wx1:
Cryo-EM structure of mouse SLC15A3 (outward-facing open)
Method: EM (single particle) / Resolution: 3.64 Å

EMDB-37898, PDB-8wx2:
Cryo-EM structure of human SLC15A3 (dimer)
Method: EM (single particle) / Resolution: 3.44 Å

EMDB-37899, PDB-8wx3:
Cryo-EM structure of human SLC15A4 (outward-facing open)
Method: EM (single particle) / Resolution: 2.83 Å

EMDB-37900, PDB-8wx4:
Cryo-EM structure of human SLC15A4 in complex with Lys-Leu (outward-facing open)
Method: EM (single particle) / Resolution: 3.12 Å

EMDB-37901, PDB-8wx5:
Cryo-EM structure of human SLC15A4 in complex with TASL (inward-facing open)
Method: EM (single particle) / Resolution: 3.91 Å

Chemicals

ChemComp-LYS:
LYSINE

ChemComp-LEU:
LEUCINE

Source
  • mus musculus (house mouse)
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Transporter / Immune system

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