Structural insights into the human system y⁺L amino acid transporter complex

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Transport

Background:

• System y+L facilitates amino acid transport via heteromeric transporters, specifically y+LAT2 (SLC7A6) or y+LAT1 (SLC7A7) complexed with 4F2hc (SLC3A2).
• The y+LAT2-4F2hc complex is crucial for amino acid exchange, supporting the glutamate-glutamine cycle and ammonia clearance.
• Upregulation of y+LAT2 by c-Myc in cancer promotes tumor growth by enhancing amino acid uptake and mTORC1 activation, yet its transport mechanism remains elusive.

Purpose of the Study:

• To elucidate the molecular mechanism of the y+LAT2-4F2hc heteromeric amino acid transporter.
• To determine the structural basis of substrate binding and transport by the y+LAT2-4F2hc complex.
• To provide insights for developing targeted therapies against y+LAT2 in cancer.

Main Methods:

• Determined cryoelectron microscopic (cryo-EM) structures of the y+LAT2-4F2hc complex bound to L-arginine (Arg) or L-leucine (Leu).
• Analyzed structural data to identify conformational changes during substrate transport.
• Performed functional assays to validate the roles of critical residues in substrate binding and transport.

Main Results:

• Obtained cryo-EM structures of y+LAT2-4F2hc at 3.60 Å (Arg-bound) and 3.58 Å (Leu-bound) resolution.
• Revealed an outward-open conformation of the transporter complex.
• Identified key residues and conformational dynamics essential for amino acid transport.

Conclusions:

• Elucidated the molecular mechanism of system y+L, specifically the y+LAT2-4F2hc transporter.
• Structural insights reveal how y+LAT2 facilitates amino acid transport.
• Provides a structural foundation for targeted therapeutic strategies against y+LAT2 in cancer.