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- EMDB-9721: human LAT1-4F2hc complex incubated with JPH203 -

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Basic information

Entry
Database: EMDB / ID: EMD-9721
Titlehuman LAT1-4F2hc complex incubated with JPH203
Map datacryo EM map
Sample
  • Complex: human LAT1-4F2hc complex incubated with JPH203
    • 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
Keywordstransporter / MEMBRANE PROTEIN
Function / homology
Function and homology information


L-tryptophan transmembrane transporter activity / alanine transport / L-tryptophan transmembrane transport / positive regulation of L-leucine import across plasma membrane / cellular response to L-arginine / thyroid hormone transmembrane transporter activity / Defective SLC7A7 causes lysinuric protein intolerance (LPI) / neutral L-amino acid secondary active transmembrane transporter activity / apical pole of neuron / amino acid import across plasma membrane ...L-tryptophan transmembrane transporter activity / alanine transport / L-tryptophan transmembrane transport / positive regulation of L-leucine import across plasma membrane / cellular response to L-arginine / thyroid hormone transmembrane transporter activity / Defective SLC7A7 causes lysinuric protein intolerance (LPI) / neutral L-amino acid secondary active transmembrane transporter activity / apical pole of neuron / amino acid import across plasma membrane / aromatic amino acid transmembrane transporter activity / tyrosine transport / L-histidine transport / amino acid transport complex / L-leucine import across plasma membrane / L-alanine transmembrane transporter activity / L-alanine import across plasma membrane / isoleucine transport / phenylalanine transport / methionine transport / L-amino acid transmembrane transporter activity / valine transport / L-leucine transmembrane transporter activity / calcium:sodium antiporter activity / thyroid hormone transport / L-leucine transport / proline transport / positive regulation of cytokine production involved in immune response / amino acid transmembrane transport / negative regulation of vascular associated smooth muscle cell apoptotic process / neutral amino acid transport / amino acid transmembrane transporter activity / external side of apical plasma membrane / Amino acid transport across the plasma membrane / neutral L-amino acid transmembrane transporter activity / Tryptophan catabolism / exogenous protein binding / anchoring junction / response to muscle activity / antiporter activity / Basigin interactions / xenobiotic transport / microvillus membrane / amino acid transport / positive regulation of interleukin-4 production / response to exogenous dsRNA / positive regulation of interleukin-17 production / tryptophan transport / transport across blood-brain barrier / response to hyperoxia / cellular response to glucose starvation / positive regulation of glial cell proliferation / negative regulation of autophagy / basal plasma membrane / liver regeneration / positive regulation of type II interferon production / peptide antigen binding / calcium ion transport / double-stranded RNA binding / melanosome / virus receptor activity / cellular response to lipopolysaccharide / basolateral plasma membrane / carbohydrate metabolic process / cadherin binding / symbiont entry into host cell / protein heterodimerization activity / apical plasma membrane / 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: 3.3 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 23, 2024-
Current statusOct 23, 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-6irs
  • Surface level: 0.07
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_9721.png

Downloads & links

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Map

FileDownload / File: emd_9721.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-0.17723757 - 0.34091938
Average (Standard dev.)-0.00011742476 (±0.0069621494)
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-0.1770.341-0.000

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Supplemental data

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Sample components

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Entire : human LAT1-4F2hc complex incubated with JPH203

EntireName: human LAT1-4F2hc complex incubated with JPH203
Components
  • Complex: human LAT1-4F2hc complex incubated with JPH203
    • 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

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Supramolecule #1: human LAT1-4F2hc complex incubated with JPH203

SupramoleculeName: human LAT1-4F2hc complex incubated with JPH203 / 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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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: 3775582
Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 480596
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 3.0)
FSC plot (resolution estimation)

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