Title : Structure of the human
LAT1-
4F2hc heteromeric amino acid transporter complex
Abstract :
- The L-type amino acid transporter 1 ( LAT1 ; also known as SLC7A5 ) catalyses the cross-membrane flux of large neutral amino acids in a sodium- and pH-independent manner1-3
- LAT1 , an antiporter of the amino acid-polyamine-organocation superfamily, also catalyses the permeation of thyroid hormones, pharmaceutical drugs, and hormone precursors such as L-3 ,4-dihydroxyphenylalanine across membranes2-6
- Overexpression of LAT1 has been observed in a wide range of tumour cells, and it is thus a potential target for anti-cancer drugs7-11
- LAT1 forms a heteromeric amino acid transporter complex with 4F2 cell-surface antigen heavy chain ( 4F2hc ; also known as SLC3A2 )-a type II membrane glycoprotein that is essential for the stability of LAT1 and for its localization to the plasma membrane8,9
- Despite extensive cell-based characterization of the LAT1- 4F2hc complex and structural determination of its homologues in bacteria, the interactions between LAT1 and 4F2hc and the working mechanism of the complex remain largely unknown12-19
- Here we report the cryo-electron microscopy structures of human LAT1- 4F2hc alone and in complex with the inhibitor 2-amino-2-norbornanecarboxylic acid at resolutions of 3.3 Å and 3.5 Å, respectively
- LAT1 exhibits an inward open conformation
- Besides a disulfide bond association, LAT1 also interacts extensively with 4F2hc on the extracellular side, within the membrane, and on the intracellular side
- Biochemical analysis reveals that 4F2hc is essential for the transport activity of the complex
- Together, our characterizations shed light on the architecture of the LAT1- 4F2hc complex, and provide insights into its function and the mechanisms through which it might be associated with disease