Molecular features of the L-type amino acid transporter 2 determine different import and export profiles for thyroid hormones and amino acids

- Characterization of different TH import and export profiles for LAT2.
- LAT2 imports but does not export 3,3′-T2.
- LAT2-features identified that determine bidirectional amino acid transport but only a unidirectional 3,3′-T2 and T3 import.
- Residue Y130 of LAT2 obstructs T4 transport and mutation of Y130 to alanine enabled T4 import.

The L-type amino acid transporter 2 (LAT2) imports amino acids (AA) and also certain thyroid hormones (TH), e.g. 3,3′-T2 and T3, but not rT3 and T4. We utilized LAT2 mutations (Y130A, N133S, F242W) that increase 3,3′-T2 import and focus here on import and export capacity for AA, T4, T3, BCH and derivatives thereof to delineate molecular features.Transport studies and analysis of competitive inhibition of import by radiolabelled TH and AA were performed in Xenopus laevis oocytes. Only Y130A, a pocket widening mutation, enabled import for T4 and increased it for T3. Mutant F242W showed increased 3,3′-T2 import but no import rates for other TH derivatives. No export was detected for any TH by LAT2-wild type (WT). Mutations Y130A and N133S enabled only the export of 3,3′-T2, while N133S also increased AA export. Thus, distinct molecular LAT2-features determine bidirectional AA transport but only an unidirectional 3,3′-T2 and T3 import.