6IRT

human LAT1-4F2hc complex bound with BCH

6IRT の概要

• エントリーDOI: 10.2210/pdb6irt/pdb
• EMDBエントリー: 9722
• 分子名称: 4F2 cell-surface antigen heavy chain, Large neutral amino acids transporter small subunit 1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• 機能のキーワード: transporter, membrane protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 130668.56

構造登録者

Yan, R.H.,Zhao, X.,Lei, J.L.,Zhou, Q. (登録日: 2018-11-14, 公開日: 2019-03-27, 最終更新日: 2024-10-16)

主引用文献

Yan, R.,Zhao, X.,Lei, J.,Zhou, Q.
Structure of the human LAT1-4F2hc heteromeric amino acid transporter complex.
Nature, 568:127-130, 2019

PubMed Abstract: 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. 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. Overexpression of LAT1 has been observed in a wide range of tumour cells, and it is thus a potential target for anti-cancer drugs. 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. 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. 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.

PubMed: 30867591
DOI: 10.1038/s41586-019-1011-z

実験手法

ELECTRON MICROSCOPY (3.5 Å)