The complete assembly of human LAT1-4F2hc complex provides insights into its regulation, function and localisation

Di Wu (), Renhong Yan, Siyuan Song, Andrew K. Swansiger, Yaning Li, James S. Prell, Qiang Zhou and Carol V. Robinson ()
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Di Wu: University of Oxford
Renhong Yan: Southern University of Science and Technology
Siyuan Song: University of Oxford
Andrew K. Swansiger: 1253 University of Oregon
Yaning Li: Tsinghua University
James S. Prell: 1253 University of Oregon
Qiang Zhou: Westlake Institute for Advanced Study; Westlake Laboratory of Life Sciences and Biomedicine
Carol V. Robinson: University of Oxford

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47948-4

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