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- EMDB-11952: Human LAT2-4F2hc complex in the apo-state -

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Basic information

Entry
Database: EMDB / ID: EMD-11952
TitleHuman LAT2-4F2hc complex in the apo-state
Map data
Sample
  • Complex: Human LAT2 4F2hc complex in the apo state
    • Protein or peptide: Large neutral amino acids transporter small subunit 2
    • Protein or peptide: Isoform 2 of 4F2 cell-surface antigen heavy chain
  • Ligand: Digitonin
Function / homology
Function and homology information


proline transmembrane transport / glycine transmembrane transporter activity / organic cation transmembrane transporter activity / glycine transport / thyroid hormone transmembrane transporter activity / neutral L-amino acid secondary active transmembrane transporter activity / amino acid import across plasma membrane / Defective SLC7A7 causes lysinuric protein intolerance (LPI) / methionine transport / tyrosine transport ...proline transmembrane transport / glycine transmembrane transporter activity / organic cation transmembrane transporter activity / glycine transport / thyroid hormone transmembrane transporter activity / neutral L-amino acid secondary active transmembrane transporter activity / amino acid import across plasma membrane / Defective SLC7A7 causes lysinuric protein intolerance (LPI) / methionine transport / tyrosine transport / L-histidine transport / apical pole of neuron / aromatic amino acid transmembrane transporter activity / amino acid transport complex / L-amino acid transmembrane transporter activity / : / L-leucine import across plasma membrane / L-alanine transmembrane transporter activity / isoleucine transport / L-alanine import across plasma membrane / phenylalanine transport / valine transport / L-leucine transmembrane transporter activity / amino acid transmembrane transport / calcium:sodium antiporter activity / L-leucine transport / thyroid hormone transport / proline transport / toxin transmembrane transporter activity / neutral amino acid transport / amino acid transmembrane transporter activity / Amino acid transport across the plasma membrane / neutral L-amino acid transmembrane transporter activity / Tryptophan catabolism / exogenous protein binding / antiporter activity / anchoring junction / Basigin interactions / microvillus membrane / amino acid transport / response to exogenous dsRNA / tryptophan transport / transport across blood-brain barrier / basal plasma membrane / calcium ion transport / peptide antigen binding / double-stranded RNA binding / melanosome / virus receptor activity / basolateral plasma membrane / carbohydrate metabolic process / cadherin binding / symbiont entry into host cell / apical plasma membrane / protein heterodimerization activity / lysosomal membrane / synapse / cell surface / protein homodimerization activity / RNA binding / extracellular exosome / nucleoplasm / membrane / plasma membrane
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 / Glycosyl hydrolase, all-beta / Glycoside hydrolase superfamily
Similarity search - Domain/homology
Amino acid transporter heavy chain SLC3A2 / Large neutral amino acids transporter small subunit 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.98 Å
AuthorsRodriguez CF / Escudero-Bravo P / Garcia-Martin C / Boskovic J / Errasti-Murugarren E / Palacin M / Llorca O
Funding support7 items
OrganizationGrant numberCountry
La Caixa FoundationLCF/PR/HR20/52400017
Ministry of Economy and Competitiveness (MINECO)SAF2015-64869-R-FEDER
Ministry of Economy and Competitiveness (MINECO)RTI2018-094211-B-100-FEDER
Ministry of Economy and Competitiveness (MINECO)SAF2017-82632-P
Ministry of Economy and Competitiveness (MINECO)BES-2015-071348
Generalitat de Catalunya2017 SGR 961
Comunidad de MadridY2018/BIO4747
CitationJournal: Proc Natl Acad Sci U S A / Year: 2021
Title: Structural basis for substrate specificity of heteromeric transporters of neutral amino acids.
Authors: Carlos F Rodriguez / Paloma Escudero-Bravo / Lucía Díaz / Paola Bartoccioni / Carmen García-Martín / Joan G Gilabert / Jasminka Boskovic / Víctor Guallar / Ekaitz Errasti-Murugarren / ...Authors: Carlos F Rodriguez / Paloma Escudero-Bravo / Lucía Díaz / Paola Bartoccioni / Carmen García-Martín / Joan G Gilabert / Jasminka Boskovic / Víctor Guallar / Ekaitz Errasti-Murugarren / Oscar Llorca / Manuel Palacín /
Abstract: Despite having similar structures, each member of the heteromeric amino acid transporter (HAT) family shows exquisite preference for the exchange of certain amino acids. Substrate specificity ...Despite having similar structures, each member of the heteromeric amino acid transporter (HAT) family shows exquisite preference for the exchange of certain amino acids. Substrate specificity determines the physiological function of each HAT and their role in human diseases. However, HAT transport preference for some amino acids over others is not yet fully understood. Using cryo-electron microscopy of apo human LAT2/CD98hc and a multidisciplinary approach, we elucidate key molecular determinants governing neutral amino acid specificity in HATs. A few residues in the substrate-binding pocket determine substrate preference. Here, we describe mutations that interconvert the substrate profiles of LAT2/CD98hc, LAT1/CD98hc, and Asc1/CD98hc. In addition, a region far from the substrate-binding pocket critically influences the conformation of the substrate-binding site and substrate preference. This region accumulates mutations that alter substrate specificity and cause hearing loss and cataracts. Here, we uncover molecular mechanisms governing substrate specificity within the HAT family of neutral amino acid transporters and provide the structural bases for mutations in LAT2/CD98hc that alter substrate specificity and that are associated with several pathologies.
History
DepositionNov 17, 2020-
Header (metadata) releaseOct 27, 2021-
Map releaseOct 27, 2021-
UpdateFeb 23, 2022-
Current statusFeb 23, 2022Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.009
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.009
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7b00
  • Surface level: 0.009
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_11952.png

Downloads & links

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Map

FileDownload / File: emd_11952.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.85 Å
Density
Contour LevelBy AUTHOR: 0.009 / Movie #1: 0.009
Minimum - Maximum-0.03537637 - 0.0555047
Average (Standard dev.)4.061789e-05 (±0.0006465394)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 326.40002 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.850.850.85
M x/y/z384384384
origin x/y/z0.0000.0000.000
length x/y/z326.400326.400326.400
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS384384384
D min/max/mean-0.0350.0560.000

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Supplemental data

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Sample components

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Entire : Human LAT2 4F2hc complex in the apo state

EntireName: Human LAT2 4F2hc complex in the apo state
Components
  • Complex: Human LAT2 4F2hc complex in the apo state
    • Protein or peptide: Large neutral amino acids transporter small subunit 2
    • Protein or peptide: Isoform 2 of 4F2 cell-surface antigen heavy chain
  • Ligand: Digitonin

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Supramolecule #1: Human LAT2 4F2hc complex in the apo state

SupramoleculeName: Human LAT2 4F2hc complex in the apo state / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293-6E

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

MacromoleculeName: Large neutral amino acids transporter small subunit 2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 58.420133 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MEEGARHRNN TEKKHPGGGE SDASPEAGSG GGGVALKKEI GLVSACGIIV GNIIGSGIFV SPKGVLENAG SVGLALIVWI VTGFITVVG ALCYAELGVT IPKSGGDYSY VKDIFGGLAG FLRLWIAVLV IYPTNQAVIA LTFSNYVLQP LFPTCFPPES G LRLLAAIC ...String:
MEEGARHRNN TEKKHPGGGE SDASPEAGSG GGGVALKKEI GLVSACGIIV GNIIGSGIFV SPKGVLENAG SVGLALIVWI VTGFITVVG ALCYAELGVT IPKSGGDYSY VKDIFGGLAG FLRLWIAVLV IYPTNQAVIA LTFSNYVLQP LFPTCFPPES G LRLLAAIC LLLLTWVNCS SVRWATRVQD IFTAGKLLAL ALIIIMGIVQ ICKGEYFWLE PKNAFENFQE PDIGLVALAF LQ GSFAYGG WNFLNYVTEE LVDPYKNLPR AIFISIPLVT FVYVFANVAY VTAMSPQELL ASNAVAVTFG EKLLGVMAWI MPI SVALST FGGVNGSLFT SSRLFFAGAR EGHLPSVLAM IHVKRCTPIP ALLFTCISTL LMLVTSDMYT LINYVGFINY LFYG VTVAG QIVLRWKKPD IPRPIKINLL FPIIYLLFWA FLLVFSLWSE PVVCGIGLAI MLTGVPVYFL GVYWQHKPKC FSDFI ELLT LVSQKMCVVV YPEVERGSGT EEANEDMEEQ QQPMYQPTPT KDKDVAGQPQ P

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Macromolecule #2: Isoform 2 of 4F2 cell-surface antigen heavy chain

MacromoleculeName: Isoform 2 of 4F2 cell-surface antigen heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 58.003652 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSQDTEVDMK EVELNELEPE KQPMNAASGA AMSLAGAEKN GLVKIKVAED EAEAAAAAKF TGLSKEELLK VAGSPGWVRT RWALLLLFW LGWLGMLAGA VVIIVRAPRC RELPAQKWWH TGALYRIGDL QAFQGHGAGN LAGLKGRLDY LSSLKVKGLV L GPIHKNQK ...String:
MSQDTEVDMK EVELNELEPE KQPMNAASGA AMSLAGAEKN GLVKIKVAED EAEAAAAAKF TGLSKEELLK VAGSPGWVRT RWALLLLFW LGWLGMLAGA VVIIVRAPRC RELPAQKWWH TGALYRIGDL QAFQGHGAGN LAGLKGRLDY LSSLKVKGLV L GPIHKNQK DDVAQTDLLQ IDPNFGSKED FDSLLQSAKK KSIRVILDLT PNYRGENSWF STQVDTVATK VKDALEFWLQ AG VDGFQVR DIENLKDASS FLAEWQNITK GFSEDRLLIA GTNSSDLQQI LSLLESNKDL LLTSSYLSDS GSTGEHTKSL VTQ YLNATG NRWCSWSLSQ ARLLTSFLPA QLLRLYQLML FTLPGTPVFS YGDEIGLDAA ALPGQPMEAP VMLWDESSFP DIPG AVSAN MTVKGQSEDP GSLLSLFRRL SDQRSKERSL LHGDFHAFSA GPGLFSYIRH WDQNERFLVV LNFGDVGLSA GLQAS DLPA SASLPAKADL LLSTQPGREE GSPLELERLK LEPHEGLLLR FPYAA

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Macromolecule #4: Digitonin

MacromoleculeName: Digitonin / type: ligand / ID: 4 / Number of copies: 1 / Formula: AJP
Molecular weightTheoretical: 1.229312 KDa
Chemical component information

ChemComp-AJP:
Digitonin / detergent*YM

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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

Concentration1.5 mg/mL
BufferpH: 7
GridModel: Quantifoil R0.6/1 / Material: COPPER / Mesh: 400
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 297 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Average electron dose: 1.0 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

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.98 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Details: CTF refinement in cisTEM / Number images used: 176132
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: BACKBONE TRACE
Output model

PDB-7b00:
Human LAT2-4F2hc complex in the apo-state

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