The complete assembly of human LAT1-4F2hc complex provides insights into its regulation, function and localisation.
Nat Commun
; 15(1): 3711, 2024 May 02.
Article
in En
| MEDLINE
| ID: mdl-38697966
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phosphatidylethanolamines
/
Fusion Regulatory Protein 1, Heavy Chain
/
Large Neutral Amino Acid-Transporter 1
/
Adaptor Proteins, Signal Transducing
/
Lipoylation
/
Membrane Proteins
Limits:
Humans
Language:
En
Journal:
Nat Commun
Journal subject:
BIOLOGIA
/
CIENCIA
Year:
2024
Document type:
Article
Affiliation country:
Reino Unido
Country of publication:
Reino Unido