{Reference Type}: Journal Article
{Title}: The complete assembly of human LAT1-4F2hc complex provides insights into its regulation, function and localisation.
{Author}: Wu D;Yan R;Song S;Swansiger AK;Li Y;Prell JS;Zhou Q;Robinson CV;
{Journal}: Nat Commun
{Volume}: 15
{Issue}: 1
{Year}: 2024 May 2
{Factor}: 17.694
{DOI}: 10.1038/s41467-024-47948-4
{Abstract}: The LAT1-4F2hc complex (SLC7A5-SLC3A2) facilitates uptake of essential amino acids, hormones and drugs. Its dysfunction is associated with many cancers and immune/neurological disorders. Here, we apply native mass spectrometry (MS)-based approaches to provide evidence of super-dimer formation (LAT1-4F2hc)2. When combined with lipidomics, and site-directed mutagenesis, we discover four endogenous phosphatidylethanolamine (PE) molecules at the interface and C-terminus of both LAT1 subunits. We find that interfacial PE binding is regulated by 4F2hc-R183 and is critical for regulation of palmitoylation on neighbouring LAT1-C187. Combining native MS with mass photometry (MP), we reveal that super-dimerization is sensitive to pH, and modulated by complex N-glycans on the 4F2hc subunit. We further validate the dynamic assemblies of LAT1-4F2hc on plasma membrane and in the lysosome. Together our results link PTM and lipid binding with regulation and localisation of the LAT1-4F2hc super-dimer.