Journal Article

Structure of the human LAT1–4F2hc heteromeric amino acid transporter complex

Yan, Renhong, Zhou, Qiang, Lei, Jianlin, Zhao, Xin

2019

Overview

The L-type amino acid transporter 1 (LAT1; also known as SLC7A5) catalyses the cross-membrane flux of large neutral amino acids in a sodium- and pH-independent manner 1 – 3 . LAT1, an antiporter of the amino acid–polyamine–organocation superfamily, also catalyses the permeation of thyroid hormones, pharmaceutical drugs, and hormone precursors such as l -3,4-dihydroxyphenylalanine across membranes 2 – 6 . Overexpression of LAT1 has been observed in a wide range of tumour cells, and it is thus a potential target for anti-cancer drugs 7 – 11 . LAT1 forms a heteromeric amino acid transporter complex with 4F2 cell-surface antigen heavy chain (4F2hc; also known as SLC3A2)—a type II membrane glycoprotein that is essential for the stability of LAT1 and for its localization to the plasma membrane 8 , 9 . Despite extensive cell-based characterization of the LAT1–4F2hc complex and structural determination of its homologues in bacteria, the interactions between LAT1 and 4F2hc and the working mechanism of the complex remain largely unknown 12 – 19 . Here we report the cryo-electron microscopy structures of human LAT1–4F2hc alone and in complex with the inhibitor 2-amino-2-norbornanecarboxylic acid at resolutions of 3.3 Å and 3.5 Å, respectively. LAT1 exhibits an inward open conformation. Besides a disulfide bond association, LAT1 also interacts extensively with 4F2hc on the extracellular side, within the membrane, and on the intracellular side. Biochemical analysis reveals that 4F2hc is essential for the transport activity of the complex. Together, our characterizations shed light on the architecture of the LAT1–4F2hc complex, and provide insights into its function and the mechanisms through which it might be associated with disease. The cryo-EM structure of the LAT1–4F2hc complex, a heteromeric amino acid transporter, is characterized, providing insights into its function and the mechanisms through which mutations of this complex could cause disease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 631/45/612/1237 / 631/535/1258/1259 / Amino acids / Amino Acids - metabolism / Analysis / Antigens / Automation / Bacteria / Binding Sites / Biochemical analysis / Biological Transport / Bonds (Securities) / Cancer / Cancer treatment / Carboxylic Acids - chemistry / Carboxylic Acids - pharmacology / Cell surface / Conformation / Cryoelectron Microscopy / Dihydroxyphenylalanine / Disulfides - chemistry / Disulfides - metabolism / Electron microscopy / Fusion Regulatory Protein 1, Heavy Chain - antagonists & inhibitors / Fusion Regulatory Protein 1, Heavy Chain - chemistry / Fusion Regulatory Protein 1, Heavy Chain - metabolism / Fusion Regulatory Protein 1, Heavy Chain - ultrastructure / Glycoproteins / Homology / Hormones / Humanities and Social Sciences / Humans / L-dopa / Large Neutral Amino Acid-Transporter 1 - chemistry / Large Neutral Amino Acid-Transporter 1 - genetics / Large Neutral Amino Acid-Transporter 1 - metabolism / Large Neutral Amino Acid-Transporter 1 - ultrastructure / Letter / Localization / Membranes / Microscopy / Models, Molecular / multidisciplinary / Multiprotein Complexes - antagonists & inhibitors / Multiprotein Complexes - chemistry / Multiprotein Complexes - metabolism / Multiprotein Complexes - ultrastructure / Norbornanes - chemistry / Norbornanes - pharmacology / Physiological aspects / Polyamines / Protein Binding / Protein Conformation / Resveratrol / Science / Science (multidisciplinary) / Sodium / Thyroid / Thyroid hormones / Transport proteins / Tumors