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- EMDB-9722: human LAT1-4F2hc complex bound with BCH -

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Basic information

Entry
Database: EMDB / ID: EMD-9722
Titlehuman LAT1-4F2hc complex bound with BCH
Map datacryo EM map
Sample
  • Complex: human LAT1-4F2hc complex bound with BCH
    • Protein or peptide: 4F2 cell-surface antigen heavy chain
    • Protein or peptide: Large neutral amino acids transporter small subunit 1
  • Ligand: 1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE
  • Ligand: (1S,2S,4R)-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid
Keywordstransporter / MEMBRANE PROTEIN
Function / homology
Function and homology information


L-tryptophan transmembrane transport / L-tryptophan transmembrane transporter activity / positive regulation of L-leucine import across plasma membrane / cellular response to L-arginine / alanine transport / thyroid hormone transmembrane transporter activity / apical pole of neuron / tyrosine transport / L-histidine transport / amino acid transport complex ...L-tryptophan transmembrane transport / L-tryptophan transmembrane transporter activity / positive regulation of L-leucine import across plasma membrane / cellular response to L-arginine / alanine transport / thyroid hormone transmembrane transporter activity / apical pole of neuron / tyrosine transport / L-histidine transport / amino acid transport complex / aromatic amino acid transmembrane transporter activity / L-leucine import across plasma membrane / L-alanine transmembrane transporter activity / L-alanine import across plasma membrane / Defective SLC7A7 causes lysinuric protein intolerance (LPI) / phenylalanine transport / isoleucine transport / methionine transport / valine transport / L-leucine transmembrane transporter activity / L-amino acid transmembrane transporter activity / amino acid import across plasma membrane / proline transport / thyroid hormone transport / L-leucine transport / amino acid transmembrane transport / negative regulation of vascular associated smooth muscle cell apoptotic process / neutral amino acid transport / positive regulation of cytokine production involved in immune response / neutral L-amino acid transmembrane transporter activity / amino acid transmembrane transporter activity / external side of apical plasma membrane / Amino acid transport across the plasma membrane / Tryptophan catabolism / exogenous protein binding / anchoring junction / antiporter activity / xenobiotic transport / Basigin interactions / microvillus membrane / response to muscle activity / amino acid transport / positive regulation of interleukin-4 production / response to exogenous dsRNA / positive regulation of interleukin-17 production / tryptophan transport / response to hyperoxia / transport across blood-brain barrier / cellular response to glucose starvation / positive regulation of glial cell proliferation / negative regulation of autophagy / basal plasma membrane / liver regeneration / peptide antigen binding / positive regulation of type II interferon production / calcium ion transport / melanosome / double-stranded RNA binding / virus receptor activity / cellular response to lipopolysaccharide / basolateral plasma membrane / carbohydrate metabolic process / cadherin binding / apical plasma membrane / protein heterodimerization activity / symbiont entry into host cell / lysosomal membrane / negative regulation of gene expression / intracellular membrane-bounded organelle / synapse / cell surface / protein homodimerization activity / RNA binding / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytosol
Similarity search - Function
L-type amino acid transporter / Solute carrier family 3 member 2, N-terminal domain / 4F2 cell-surface antigen heavy chain / Solute carrier family 3 member 2 N-terminus / : / Amino acid/polyamine transporter I / Amino acid permease / Alpha amylase, catalytic domain / Glycosyl hydrolase, family 13, catalytic domain / Alpha-amylase domain ...L-type amino acid transporter / Solute carrier family 3 member 2, N-terminal domain / 4F2 cell-surface antigen heavy chain / Solute carrier family 3 member 2 N-terminus / : / Amino acid/polyamine transporter I / Amino acid permease / Alpha amylase, catalytic domain / Glycosyl hydrolase, family 13, catalytic domain / Alpha-amylase domain / Glycosyl hydrolase, all-beta / Glycoside hydrolase superfamily
Similarity search - Domain/homology
Amino acid transporter heavy chain SLC3A2 / Large neutral amino acids transporter small subunit 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsYan RH / Zhao X
Funding support China, 6 items
OrganizationGrant numberCountry
Ministry of Science and Technology (China)2016YFA0500402 China
Ministry of Science and Technology (China)2016YFA0501100 China
Ministry of Science and Technology (China)2015CB910101 China
National Natural Science Foundation of China31621092 China
National Natural Science Foundation of China31630017 China
National Natural Science Foundation of China81861138009 China
CitationJournal: Nature / Year: 2019
Title: Structure of the human LAT1-4F2hc heteromeric amino acid transporter complex.
Authors: Renhong Yan / Xin Zhao / Jianlin Lei / Qiang Zhou /
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 ...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.
History
DepositionNov 14, 2018-
Header (metadata) releaseMar 27, 2019-
Map releaseMar 27, 2019-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.07
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.07
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6irt
  • Surface level: 0.07
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_9722.png

Downloads & links

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Map

FileDownload / File: emd_9722.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcryo EM map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.09 Å/pix.
x 256 pix.
= 279.296 Å		1.09 Å/pix.
x 256 pix.
= 279.296 Å		1.09 Å/pix.
x 256 pix.
= 279.296 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.091 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.07 / Movie #1: 0.07
Minimum - Maximum-0.14636704 - 0.26985458
Average (Standard dev.)-0.00037111546 (±0.0062699076)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 279.296 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0911.0911.091
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z279.296279.296279.296
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ300300300
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.1460.270-0.000

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Supplemental data

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Sample components

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Entire : human LAT1-4F2hc complex bound with BCH

EntireName: human LAT1-4F2hc complex bound with BCH
Components
  • Complex: human LAT1-4F2hc complex bound with BCH
    • Protein or peptide: 4F2 cell-surface antigen heavy chain
    • Protein or peptide: Large neutral amino acids transporter small subunit 1
  • Ligand: 1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE
  • Ligand: (1S,2S,4R)-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid

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Supramolecule #1: human LAT1-4F2hc complex bound with BCH

SupramoleculeName: human LAT1-4F2hc complex bound with BCH / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 100 KDa

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Macromolecule #1: 4F2 cell-surface antigen heavy chain

MacromoleculeName: 4F2 cell-surface antigen heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 70.160828 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAHHHHHHHH HHSGRELQPP EASIAVVSIP RQLPGSHSEA GVQGLSAGDD SETGSDCVTQ AGLQLLASSD PPALASKNAE VTVETGFHH VSQADIEFLT SIDPTASASG SAGITGTMSQ DTEVDMKEVE LNELEPEKQP MNAASGAAMS LAGAEKNGLV K IKVAEDEA ...String:
MAHHHHHHHH HHSGRELQPP EASIAVVSIP RQLPGSHSEA GVQGLSAGDD SETGSDCVTQ AGLQLLASSD PPALASKNAE VTVETGFHH VSQADIEFLT SIDPTASASG SAGITGTMSQ DTEVDMKEVE LNELEPEKQP MNAASGAAMS LAGAEKNGLV K IKVAEDEA EAAAAAKFTG LSKEELLKVA GSPGWVRTRW ALLLLFWLGW LGMLAGAVVI IVRAPRCREL PAQKWWHTGA LY RIGDLQA FQGHGAGNLA GLKGRLDYLS SLKVKGLVLG PIHKNQKDDV AQTDLLQIDP NFGSKEDFDS LLQSAKKKSI RVI LDLTPN YRGENSWFST QVDTVATKVK DALEFWLQAG VDGFQVRDIE NLKDASSFLA EWQNITKGFS EDRLLIAGTN SSDL QQILS LLESNKDLLL TSSYLSDSGS TGEHTKSLVT QYLNATGNRW CSWSLSQARL LTSFLPAQLL RLYQLMLFTL PGTPV FSYG DEIGLDAAAL PGQPMEAPVM LWDESSFPDI PGAVSANMTV KGQSEDPGSL LSLFRRLSDQ RSKERSLLHG DFHAFS AGP GLFSYIRHWD QNERFLVVLN FGDVGLSAGL QASDLPASAS LPAKADLLLS TQPGREEGSP LELERLKLEP HEGLLLR FP YAALE

UniProtKB: Amino acid transporter heavy chain SLC3A2

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Macromolecule #2: Large neutral amino acids transporter small subunit 1

MacromoleculeName: Large neutral amino acids transporter small subunit 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 57.244934 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MADYKDDDDK SGPDEVDASG RAGAGPKRRA LAAPAAEEKE EAREKMLAAK SADGSEPAGE GEGVTLQRNI TLLNGVAIIV GTIIGSGIF VTPTGVLKEA GSPGLALVVW AACGVFSIVG ALCYAELGTT ISKSGGDYAY MLEVYGSLPA FLKLWIELLI I RPSSQYIV ...String:
MADYKDDDDK SGPDEVDASG RAGAGPKRRA LAAPAAEEKE EAREKMLAAK SADGSEPAGE GEGVTLQRNI TLLNGVAIIV GTIIGSGIF VTPTGVLKEA GSPGLALVVW AACGVFSIVG ALCYAELGTT ISKSGGDYAY MLEVYGSLPA FLKLWIELLI I RPSSQYIV ALVFATYLLK PLFPTCPVPE EAAKLVACLC VLLLTAVNCY SVKAATRVQD AFAAAKLLAL ALIILLGFVQ IG KGDVSNL DPNFSFEGTK LDVGNIVLAL YSGLFAYGGW NYLNFVTEEM INPYRNLPLA IIISLPIVTL VYVLTNLAYF TTL STEQML SSEAVAVDFG NYHLGVMSWI IPVFVGLSCF GSVNGSLFTS SRLFFVGSRE GHLPSILSMI HPQLLTPVPS LVFT CVMTL LYAFSKDIFS VINFFSFFNW LCVALAIIGM IWLRHRKPEL ERPIKVNLAL PVFFILACLF LIAVSFWKTP VECGI GFTI ILSGLPVYFF GVWWKNKPKW LLQGIFSTTV LCQKLMQVVP QET

UniProtKB: Large neutral amino acids transporter small subunit 1

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Macromolecule #4: 1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE

MacromoleculeName: 1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE / type: ligand / ID: 4 / Number of copies: 2 / Formula: 3PH
Molecular weightTheoretical: 704.998 Da
Chemical component information

ChemComp-3PH:
1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE

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Macromolecule #5: (1S,2S,4R)-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid

MacromoleculeName: (1S,2S,4R)-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid
type: ligand / ID: 5 / Number of copies: 1 / Formula: AUU
Molecular weightTheoretical: 155.194 Da
Chemical component information

ChemComp-AUU:
(1S,2S,4R)-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 48.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1247297
Startup modelType of model: INSILICO MODEL
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 262949
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 3.0)
FSC plot (resolution estimation)

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