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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.

Original publication




Journal article


Nat Commun

Publication Date





Humans, Large Neutral Amino Acid-Transporter 1, Phosphatidylethanolamines, Lipoylation, Lysosomes, Cell Membrane, Amino Acid Transport System y+, HEK293 Cells, Protein Multimerization, Protein Binding, Mass Spectrometry, Mutagenesis, Site-Directed, Hydrogen-Ion Concentration, Membrane Proteins, Fusion Regulatory Protein 1, Heavy Chain, Adaptor Proteins, Signal Transducing