The complete assembly of human LAT1-4F2hc complex provides insights into its regulation, function and localisation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38697966.
- Also identified by DOI 10.1038/s41467-024-47948-4 and PMC identifier 11065870.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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)<sub>2</sub>. 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.
Medical subject headings
- Large Neutral Amino Acid-Transporter 1
- Phosphatidylethanolamines
- Lipoylation
- Membrane Proteins
- Fusion Regulatory Protein 1, Heavy Chain
- Adaptor Proteins, Signal Transducing