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

Autor: Wu D; Department of Chemistry, University of Oxford, Oxford, OX1 3QZ, UK. di.wu2@chem.ox.ac.uk.; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, OX1 3QU, UK. di.wu2@chem.ox.ac.uk., Yan R; Department of Biochemistry, Key University Laboratory of Metabolism and Health of Guangdong, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, Guangdong Province, China., Song S; Department of Chemistry, University of Oxford, Oxford, OX1 3QZ, UK.; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, OX1 3QU, UK., Swansiger AK; Department of Chemistry and Biochemistry, 1253 University of Oregon, Eugene, Oregon, 97403-1253, USA., Li Y; Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, China., Prell JS; Department of Chemistry and Biochemistry, 1253 University of Oregon, Eugene, Oregon, 97403-1253, USA., Zhou Q; Research Center for Industries of the Future, Zhejiang Key Laboratory of Structural Biology, School of Life Sciences, Westlake University; Institute of Biology, Westlake Institute for Advanced Study; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, 310024, Zhejiang Province, China., Robinson CV; Department of Chemistry, University of Oxford, Oxford, OX1 3QZ, UK. carol.robinson@chem.ox.ac.uk.; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, OX1 3QU, UK. carol.robinson@chem.ox.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 May 02; Vol. 15 (1), pp. 3711. Date of Electronic Publication: 2024 May 02.
DOI: 10.1038/s41467-024-47948-4
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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