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TitleStructural insights into the human system yL amino acid transporter complex.
Journal, issue, pagesStructure, Vol. 33, Issue 7, Page 1224-11232.e5, Year 2025
Publish dateJul 3, 2025
AuthorsLu Dai / Kangtai Xu / Ting Zhang / Xiaoting Wang / Qian Zeng / Hao Liang / Chenye Xu / Liuqing Yang / Zilong Wang / Renhong Yan /
PubMed AbstractSystem yL facilitates the sodium-independent transport of cationic and sodium-dependent transport of neutral amino acids via heteromeric amino acid transporters. System yL consists of either SLC7A6 ...System yL facilitates the sodium-independent transport of cationic and sodium-dependent transport of neutral amino acids via heteromeric amino acid transporters. System yL consists of either SLC7A6 (yLAT2) or SLC7A7 (yLAT1) and 4F2hc (SLC3A2). The yLAT2-4F2hc complex mediates the exchange of -lysine (Lys), -arginine (Arg), -leucine (Leu), and -glutamine (Gln) and is important for the glutamate-glutamine cycle and ammonia clearance. c-Myc-driven upregulation of yLAT2 in cancer enhances amino acid uptake and mTORC1 activation, promoting tumor growth. Its transport mechanism has remained unclear. Here, we determined the cryoelectron microscopic (cryo-EM) structures of the yLAT2-4F2hc complex bound to either Arg or Leu at 3.60 Å and 3.58 Å resolution, respectively, revealing an outward-open conformation. Our structural analysis highlights conformational changes during transport, and functional assays validate critical residues involved in substrate binding and transport. These findings elucidate the molecular mechanism of the system yL and provide a foundation for developing targeted therapies against yLAT2.
External linksStructure / PubMed:40347950
MethodsEM (single particle)
Resolution3.58 - 3.6 Å
Structure data

62640

9ky5

EMDB-62640, PDB-9ky5:
Structure of y+LAT2 bound with Arg
Method: EM (single particle) / Resolution: 3.6 Å

63006

9ldr

EMDB-63006, PDB-9ldr:
Overall structure of the y+LAT2-4F2hc bound with Leu
Method: EM (single particle) / Resolution: 3.58 Å

Chemicals

ChemComp-ARG:
ARGININE

ChemComp-LEU:
LEUCINE

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / complex / amino acid / transporter

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