2.A.3.8.25
Large neutral amino acids transporter small subunit 1 (4F2 light chain) (4F2 LC) (4F2LC) (CD98 light chain; SLC3A2; LAT1) (Integral membrane protein E16) (L-type amino acid transporter 1) (hLAT1) (Solute carrier family 7 member 5) (y+ system cationic and neutral amino acid transporter).  The heavy chain, CD98hc, modulates integrin signaling, plays a role in cell-to-cell fusion, and is essential for Brucella infection (Keriel et al. 2015).  In addition to several large neutral L-amino acids, Lat1 in conjunction with 4F2hc, transports S-nitroso-L-cysteine (Li and Whorton 2007), is important for transport of certain drugs into the brain, and is important for cancer (Lee et al. 2019). LAT1/CD98 mediates a Na⁺ and pH-independent antiport of amino acids (Scalise et al. 2018). It has been demonstrated that the preferred substrate is histidine, but many large amino acids are also sustrates. CD98 is not required for transport, being plausibly involved in routing LAT1 to the plasma membrane. Homology models have been built on the basis of the AdiC transporter from E.coli. Crucial residues for substrate recognition and gating have been identified using a combined approach of bioinformatics and site-directed mutagenesis coupled to functional assays. LAT1 is involved in important human diseases such as neurological disorders and cancer (Scalise et al. 2018). The cryo-EM structure of the human LAT1-CD98hc heterodimer at 3.3-A resolution has been determined (Lee et al. 2019). LAT1 features a canonical Leu T-fold and exhibits an unusual loop structure on transmembrane helix 6, creating an extended cavity that might accommodate bulky amino acids and drugs. CD98hc engages with LAT1 through extracellular, transmembrane and putative cholesterol-mediated interactions. The SLC7A5 (LAT1) gene, which encodes the main transmembrane transporter of large neutral amino acids and of thyroid hormones, exists as variants, one of which is responsible for obesity in patients with phenylketonuria (Bik-Multanowski et al. 2020). SLC7A5 functions in mTORC1 ativation in late endosomes (Jin et al. 2021). It is the main transporter for phenylalanine, and management precautions for risk of obesity are necessary among infants with PKU carrying the rs113883650 variant of the LAT1 gene (Bik-Multanowski et al. 2022). CD98hc is expressed in pancreatic ductal adenocarcinomas in increased amounts (Bianconi et al. 2022). Human LAT1 (SLC7A5) transports amino acids, thyroid hormones, and drugs such as the Parkinson's disease drug levodopa (L-Dopa). It is found in the blood-brain barrier, testis, bone marrow, and placenta, and its dysregulation has been associated with various neurological diseases, such as autism and epilepsy, as well as cancer (Hutchinson et al. 2022). The inhibitor specificities of LAT1 have been described (Hutchinson et al. 2022). SLC7A5 and SLC7A11 can be manipuated to eliminate the barrier to successful CAR-T therapy (Panetti et al. 2022).  Targeting glutamine metabolic reprogramming of SLC7A5 enhances the efficacy of anti-PD-1 in triple-negative breast cancer (Huang et al. 2023). The human LAT1-4F2hc (SLC7A5-SLC3A2) transporter complex has been implicated in physiological and pathophysiological characteristics (Kahlhofer and Teis 2022).  Four cholesterol-binding sites (CHOL1-4) were identified in a recent LAT1-apo inward-open conformation cryo-EM structure. Hutchinson and Schlessinger 2024 explored the interactions between LAT1 and cholesterol. Their findings suggested that CHOL3 forms the most stable and favorable interactions within LAT1. Fat mass and obesity-associated protein (FTO) mediated m⁶A modification of circFAM192A promotes gastric cancer proliferation by suppressing SLC7A5 decay (Wu et al. 2024). FXR, MRP-1 and SLC7A5 are new targets for the treatment of hepatocellular carcinoma (Zhang et al. 2024).