The human LAT1-4F2hc (SLC7A5-SLC3A2) transporter complex: Physiological and pathophysiological implications

Abstract

LAT1 and 4F2hc form a heterodimeric membrane protein complex, which functions as one of the best characterized amino acid transporters. Since LAT1-4F2hc is required for the efficient uptake of essential amino acids and hormones, it promotes cellular growth, in part, by stimulating mTORC1 (mechanistic target of rapamycin complex 1) signalling and by repressing the integrated stress response (ISR). Gain or loss of LAT1-4F2hc function is associated with cancer, diabetes, and immunological and neurological diseases. Hence, LAT1-4F2hc represents an attractive drug target for disease treatment. Specific targeting of LAT1-4F2hc will be facilitated by the increasingly detailed understanding of its molecular architecture, which provides important concepts for its function and regulation. Here, we summarize (i) structural insights that help to explain how LAT1 and 4F2hc assemble to transport amino acids across membranes, (ii) the role of LAT1-4F2hc in key metabolic signalling pathways, and (iii) how derailing these processes could contribute to diseases.

Keywords: 4F2hc; LAT1; disease; integrated stress response; mTORC1.

FIGURE 1

Cartoon of the structural model for LAT1–4F2hc. (A) Structural model of LAT1–4F2hc in an inward‐open confirmation (model based on cryo‐EM: PDB ID: 6IRT ³⁰ ) 4F2hc is depicted in green, LAT1 in orange and the residues Phe252 and Gly255 are highlighted in light green. (B) The cartoon depicts a possible transport mechanism of LAT1–4F2hc. In the inward‐open state, substrates from the intracellular side are able to bind to LAT1, inducing the rotation of TM1a and TM6b towards the hash domain to close the gate. (C) In the outward‐open state, TM1b and TM6a are further rotating, leading to substrate release. The extracellular domain of 4F2hc is also rotating, stabilizing LAT1 (model according to structural analysis from previous works ³⁰ , ⁴⁰ , ⁴¹ ). 4F2hc is depicted in blue, parts of LAT1 are depicted in grew. TM6a and b of LAT1 are depicted in dark red, whereas TM1b and a are depicted in light red.

FIGURE 2

LAT1–4F2hc in mTORC1 signalling and the intergraded stress response. Cartoon showing components of the nutrient‐sensing as well as growth factor sensing pathway upstream of mTORC1. LAT1–4F2hc mediated leucine uptake activates mTORC1 via the amino acid sensors Sestrin1/2 and LRS. The amino acid stress response pathway is part of the ISR. Amino acid deprivation induces the accumulation of uncharged tRNAs. Activated GCN2 phosphorylates eIF2α. In turn, global protein translation is inhibited and the transcription factor ATF4 is preferentially translated. ATF4 controls the expression of LAT1.