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- EMDB-0679: human LAT1-4F2hc complex bound with BCH, focused refined on BCH -

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Basic information

Entry
Database: EMDB / ID: EMD-0679
Titlehuman LAT1-4F2hc complex bound with BCH, focused refined on BCH
Map data
Sample
  • Complex: human LAT1-4F2hc complex bound with BCH
    • Protein or peptide: LAT1
    • Protein or peptide: 4F2hc4F2 cell-surface antigen heavy chain
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 / amino acid import across plasma membrane / methionine transport / tyrosine transport / L-histidine transport ...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 / amino acid import across plasma membrane / methionine transport / tyrosine transport / L-histidine transport / aromatic amino acid transmembrane transporter activity / amino acid transport complex / L-amino acid transmembrane transporter activity / : / L-leucine import across plasma membrane / isoleucine transport / phenylalanine transport / valine transport / L-leucine transmembrane transporter activity / amino acid transmembrane transport / positive regulation of cytokine production involved in immune response / L-leucine transport / thyroid hormone transport / proline transport / neutral amino acid transport / negative regulation of vascular associated smooth muscle cell apoptotic process / amino acid transmembrane transporter activity / Amino acid transport across the plasma membrane / external side of apical plasma membrane / neutral L-amino acid transmembrane transporter activity / Tryptophan catabolism / xenobiotic transport / antiporter activity / response to muscle activity / Basigin interactions / microvillus membrane / positive regulation of interleukin-4 production / 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 / peptide antigen binding / positive regulation of type II interferon production / basolateral plasma membrane / cellular response to lipopolysaccharide / apical plasma membrane / lysosomal membrane / negative regulation of gene expression / intracellular membrane-bounded organelle / extracellular exosome / membrane / plasma membrane / cytosol
Similarity search - Function
L-type amino acid transporter / Amino acid/polyamine transporter I / Amino acid permease
Similarity search - Domain/homology
Large neutral amino acids transporter small subunit 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsYan RH / Zhao X / Lei JL / Zhou Q
Funding support China, 6 items
OrganizationGrant numberCountry
Ministry of Science and Technology (China)2016YFA0500402 China
Ministry of Science and Technology (China)2015CB910101 China
Ministry of Science and Technology (China)2016YFA0501100 China
National Natural Science Foundation of China31630017 China
National Natural Science Foundation of China31621092 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
DepositionJan 10, 2019-
Header (metadata) releaseMar 27, 2019-
Map releaseMar 27, 2019-
UpdateNov 6, 2019-
Current statusNov 6, 2019Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.05
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.05
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_0679.png

Downloads & links

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Map

FileDownload / File: emd_0679.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.091 Å
Density
Contour LevelBy AUTHOR: 0.05 / Movie #1: 0.05
Minimum - Maximum-0.23046674 - 0.336508
Average (Standard dev.)-0.00034262522 (±0.005962923)
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
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.2300.337-0.000

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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: LAT1
    • Protein or peptide: 4F2hc4F2 cell-surface antigen heavy chain

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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: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
Molecular weightTheoretical: 100 KDa

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Macromolecule #1: LAT1

MacromoleculeName: LAT1 / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MADYKDDDDK SGPDEVDASG RAGAGPKRRA LAAPAAEEKE EAREKMLAAK SADGSEPAGE GEGVTLQRNI TLLNGVAIIV GTIIGSGIF VTPTGVLKEA GSPGLALVVW AACGVFSIVG ALCYAELGTT ISKSGGDYAY M LEVYGSLP AFLKLWIELL IIRPSSQYIV ...String:
MADYKDDDDK SGPDEVDASG RAGAGPKRRA LAAPAAEEKE EAREKMLAAK SADGSEPAGE GEGVTLQRNI TLLNGVAIIV GTIIGSGIF VTPTGVLKEA GSPGLALVVW AACGVFSIVG ALCYAELGTT ISKSGGDYAY M LEVYGSLP AFLKLWIELL IIRPSSQYIV ALVFATYLLK PLFPTCPVPE EAAKLVACLC VL LLTAVNC YSVKAATRVQ DAFAAAKLLA LALIILLGFV QIGKGDVSNL DPNFSFEGTK LDV GNIVLA LYSGLFAYGG WNYLNFVTEE MINPYRNLPL AIIISLPIVT LVYVLTNLAY FTTL STEQM LSSEAVAVDF GNYHLGVMSW IIPVFVGLSC FGSVNGSLFT SSRLFFVGSR EGHLP SILS MIHPQLLTPV PSLVFTCVMT LLYAFSKDIF SVINFFSFFN WLCVALAIIG MIWLRH RKP ELERPIKVNL ALPVFFILAC LFLIAVSFWK TPVECGIGFT IILSGLPVYF FGVWWKN KP KWLLQGIFST TVLCQKLMQV VPQET

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Macromolecule #2: 4F2hc

MacromoleculeName: 4F2hc / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAHHHHHHHH HHSGRELQPP EASIAVVSIP RQLPGSHSEA GVQGLSAGDD SETGSDCVTQ AGLQLLASSD PPALASKNAE VTVETGFHHV SQADI EFLT SIDPTASASG SAGITGTMSQ DTEVDMKEVE LNELEPEKQP MNAASGAAMS LAGAEKNGLV KIKVAEDEAE ...String:
MAHHHHHHHH HHSGRELQPP EASIAVVSIP RQLPGSHSEA GVQGLSAGDD SETGSDCVTQ AGLQLLASSD PPALASKNAE VTVETGFHHV SQADI EFLT SIDPTASASG SAGITGTMSQ DTEVDMKEVE LNELEPEKQP MNAASGAAMS LAGAEKNGLV KIKVAEDEAE AAAAAK FTG LSKEELLKVA GSPGWVRTRW ALLLLFWLGW LGMLAGAVVI IVRAPRCREL PAQKWWHTGA LYRIGDLQAF QGHGAGN LA GLKGRLDYLS SLKVKGLVLG PIHKNQKDDV AQTDLLQIDP NFGSKEDFDS LLQSAKKKSI RVILDLTPNY RGENSWFS T QVDTVATKVK DALEFWLQAG VDGFQVRDIE NLKDASSFLA EWQNITKGFS EDRLLIAGTN SSDLQQILSL LESNKDLLL TSSYLSDSGS TGEHTKSLVT QYLNATGNRW CSWSLSQARL LTSFLPAQLL RLYQLMLFTL PGTPVFSYGD EIGLDAAALP GQPMEAPVM LWDESSFPDI PGAVSANMTV KGQSEDPGSL LSLFRRLSDQ RSKERSLLHG DFHAFSAGPG LFSYIRHWDQ N ERFLVVLN FGDVGLSAGL QASDLPASAS LPAKADLLLS TQPGREEGSP LELERLKLEP HEGLLLRFPY AALE

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

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Image processing

Particle selectionNumber selected: 1247297
CTF correctionSoftware - Name: Gctf
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 3.0)
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 262949

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