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- EMDB-9849: LAT1-CD98hc complex bound to MEM-108 Fab -

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Basic information

Entry
Database: EMDB / ID: EMD-9849
TitleLAT1-CD98hc complex bound to MEM-108 Fab
Map dataSharpened, masked map
Sample
  • Complex: LAT1-CD98hc complex bound to MEM-108 Fab
    • Protein or peptide: Large neutral amino acids transporter small subunit 1
    • Protein or peptide: 4F2 cell-surface antigen heavy chain
    • Protein or peptide: Antibody
    • Protein or peptide: Antibody
  • Ligand: CHOLESTEROL
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsTransporter / Glycoprotein / Complex / MEMBRANE PROTEIN / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
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) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.31 Å
AuthorsLee Y / Nishizawa T
Funding support Japan, 2 items
OrganizationGrant numberCountry
Japan Society for the Promotion of ScienceJP16J07405 Japan
Japan Agency for Medical Research and Development (AMED)JP18am0101115 Japan
CitationJournal: Nat Struct Mol Biol / Year: 2019
Title: Cryo-EM structure of the human L-type amino acid transporter 1 in complex with glycoprotein CD98hc.
Authors: Yongchan Lee / Pattama Wiriyasermkul / Chunhuan Jin / Lili Quan / Ryuichi Ohgaki / Suguru Okuda / Tsukasa Kusakizako / Tomohiro Nishizawa / Kazumasa Oda / Ryuichiro Ishitani / Takeshi ...Authors: Yongchan Lee / Pattama Wiriyasermkul / Chunhuan Jin / Lili Quan / Ryuichi Ohgaki / Suguru Okuda / Tsukasa Kusakizako / Tomohiro Nishizawa / Kazumasa Oda / Ryuichiro Ishitani / Takeshi Yokoyama / Takanori Nakane / Mikako Shirouzu / Hitoshi Endou / Shushi Nagamori / Yoshikatsu Kanai / Osamu Nureki /
Abstract: The L-type amino acid transporter 1 (LAT1 or SLC7A5) transports large neutral amino acids across the membrane and is crucial for brain drug delivery and tumor growth. LAT1 forms a disulfide-linked ...The L-type amino acid transporter 1 (LAT1 or SLC7A5) transports large neutral amino acids across the membrane and is crucial for brain drug delivery and tumor growth. LAT1 forms a disulfide-linked heterodimer with CD98 heavy chain (CD98hc, 4F2hc or SLC3A2), but the mechanism of assembly and amino acid transport are poorly understood. Here we report the cryo-EM structure of the human LAT1-CD98hc heterodimer at 3.3-Å resolution. LAT1 features a canonical Leu T-fold and exhibits an unusual loop structure on transmembrane helix 6, creating an extended cavity that might accommodate bulky amino acids and drugs. CD98hc engages with LAT1 through the extracellular, transmembrane and putative cholesterol-mediated interactions. We also show that two anti-CD98 antibodies recognize distinct, multiple epitopes on CD98hc but not its glycans, explaining their robust reactivities. These results reveal the principles of glycoprotein-solute carrier assembly and provide templates for improving preclinical drugs and antibodies targeting LAT1 or CD98hc.
History
DepositionMar 13, 2019-
Header (metadata) releaseJun 19, 2019-
Map releaseJun 19, 2019-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.055
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.055
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6jmq
  • Surface level: 0.055
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_9849.png

Downloads & links

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Map

FileDownload / File: emd_9849.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened, masked map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.33 Å/pix.
x 288 pix.
= 383.904 Å		1.33 Å/pix.
x 288 pix.
= 383.904 Å		1.33 Å/pix.
x 288 pix.
= 383.904 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.333 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.055 / Movie #1: 0.055
Minimum - Maximum-0.19095844 - 0.31260988
Average (Standard dev.)0.00009340672 (±0.0034436851)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 383.904 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.3331.3331.333
M x/y/z288288288
origin x/y/z0.0000.0000.000
length x/y/z383.904383.904383.904
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ858858858
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS288288288
D min/max/mean-0.1910.3130.000

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Supplemental data

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Mask #1

Fileemd_9849_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2 used for FSC calculation. The...

Fileemd_9849_half_map_1.map
AnnotationHalf map 2 used for FSC calculation. The header contains a wrong pixel size information (1.375 A). The correct pixel size is 1.333 A.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 1 used for FSC calculation. The...

Fileemd_9849_half_map_2.map
AnnotationHalf map 1 used for FSC calculation. The header contains a wrong pixel size information (1.375 A). The correct pixel size is 1.333 A.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : LAT1-CD98hc complex bound to MEM-108 Fab

EntireName: LAT1-CD98hc complex bound to MEM-108 Fab
Components
  • Complex: LAT1-CD98hc complex bound to MEM-108 Fab
    • Protein or peptide: Large neutral amino acids transporter small subunit 1
    • Protein or peptide: 4F2 cell-surface antigen heavy chain
    • Protein or peptide: Antibody
    • Protein or peptide: Antibody
  • Ligand: CHOLESTEROL
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: LAT1-CD98hc complex bound to MEM-108 Fab

SupramoleculeName: LAT1-CD98hc complex bound to MEM-108 Fab / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 175 kDa/nm

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

MacromoleculeName: Large neutral amino acids transporter small subunit 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 56.043746 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAGAGPKRRA LAAPAAEEKE EAREKMLAAK SADGSAPAGE GEGVTLQRNI TLLNGVAIIV GTIIGSGIFV TPTGVLKEAG SPGLALVVW AACGVFSIVG ALCYAELGTT ISKSGGDYAY MLEVYGSLPA FLKLWIELLI IRPSSQYIVA LVFATYLLKP L FPTCPVPE ...String:
MAGAGPKRRA LAAPAAEEKE EAREKMLAAK SADGSAPAGE GEGVTLQRNI TLLNGVAIIV GTIIGSGIFV TPTGVLKEAG SPGLALVVW AACGVFSIVG ALCYAELGTT ISKSGGDYAY MLEVYGSLPA FLKLWIELLI IRPSSQYIVA LVFATYLLKP L FPTCPVPE EAAKLVACLC VLLLTAVNCY SVKAATRVQD AFAAAKLLAL ALIILLGFVQ IGKGDVSNLD PNFSFEGTKL DV GNIVLAL YSGLFAYGGW NYLNFVTEEM INPYRNLPLA IIISLPIVTL VYVLTNLAYF TTLSTEQMLS SEAVAVDFGN YHL GVMSWI IPVFVGLSCF GSVNGSLFTS SRLFFVGSRE GHLPSILSMI HPQLLTPVPS LVFTCVMTLL YAFSKDIFSV INFF SFFNW LCVALAIIGM IWLRHRKPEL ERPIKVNLAL PVFFILACLF LIAVSFWKTP VECGIGFTII LSGLPVYFFG VWWKN KPKW LLQGIFSTTV LCQKLMQVVP QETDYKDDDD K

UniProtKB: Large neutral amino acids transporter small subunit 1

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

MacromoleculeName: 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: 68.069625 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GSELQPPEAS IAVVSIPRQL PGSHSEAGVQ GLSAGDDSEL GSHCVAQTGL ELLASGDPLP SASQNAEMIE TGSDCVTQAG LQLLASSDP PALASKNAEV TGTMSQDTEV DMKEVELNEL EPEKQPMNAA SGAAMSLAGA EKNGLVKIKV AEDEAEAAAA A KFTGLSKE ...String:
GSELQPPEAS IAVVSIPRQL PGSHSEAGVQ GLSAGDDSEL GSHCVAQTGL ELLASGDPLP SASQNAEMIE TGSDCVTQAG LQLLASSDP PALASKNAEV TGTMSQDTEV DMKEVELNEL EPEKQPMNAA SGAAMSLAGA EKNGLVKIKV AEDEAEAAAA A KFTGLSKE ELLKVAGSPG WVRTRWALLL LFWLGWLGML AGAVVIIVRA PRCRELPAQK WWHTGALYRI GDLQAFQGHG AG NLAGLKG RLDYLSSLKV KGLVLGPIHK NQKDDVAQTD LLQIDPNFGS KEDFDSLLQS AKKKSIRVIL DLTPNYRGEN SWF STQVDT VATKVKDALE FWLQAGVDGF QVRDIENLKD ASSFLAEWQN ITKGFSEDRL LIAGTNSSDL QQILSLLESN KDLL LTSSY LSDSGSTGEH TKSLVTQYLN ATGNRWCSWS LSQARLLTSF LPAQLLRLYQ LMLFTLPGTP VFSYGDEIGL DAAAL PGQP MEAPVMLWDE SSFPDIPGAV SANMTVKGQS EDPGSLLSLF RRLSDQRSKE RSLLHGDFHA FSAGPGLFSY IRHWDQ NER FLVVLNFGDV GLSAGLQASD LPASASLPAK ADLLLSTQPG REEGSPLELE RLKLEPHEGL LLRFPYAA

UniProtKB: Amino acid transporter heavy chain SLC3A2

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Macromolecule #3: Antibody

MacromoleculeName: Antibody / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 22.577857 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: QVQLKESGPG LVAPSQSLSI TCTVSGFPLT (UNK)(UNK)(UNK)(UNK)(UNK)WVRQP PGKGLEWLG(UNK) (UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)RLSI SKDNSK SQV FLKMNSLQTD ...String:
QVQLKESGPG LVAPSQSLSI TCTVSGFPLT (UNK)(UNK)(UNK)(UNK)(UNK)WVRQP PGKGLEWLG(UNK) (UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)RLSI SKDNSK SQV FLKMNSLQTD DTARYYCAR(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)W GQGTSVT VS SAKTTPPSVY PLAPGS(UNK)(UNK)(UNK)(UNK) (UNK)SMVTLGCLV KGYFPEPVTV TWNSGSLSSG VHTFPAVL Q SDLYTLSSSV TVPSSTWPSE TVTCNVAHPA SSTKVDKKIV PRD

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Macromolecule #4: Antibody

MacromoleculeName: Antibody / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.227152 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: DIVMSQSPSS LVVSVGEKVT MSC(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) (UNK)WYQQKPGQS PKLLIY(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) GVPDRF TGSGSGTDFT ...String:
DIVMSQSPSS LVVSVGEKVT MSC(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) (UNK)WYQQKPGQS PKLLIY(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) GVPDRF TGSGSGTDFT LTISSVKAED LAVYYC(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)FGG G TKLEIKRADA APTVSIFPPS SEQLTSGGAS VVCFLNNFYP KDINVKWKID GSERQNGVLN SWTDQDSKDS TYSMSSTLT LTKDEYERHN SYTCEATHKT STSPIVKSFN RNE

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Macromolecule #6: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 6 / Number of copies: 5 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 3 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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: FEI FALCON III (4k x 4k) / Average electron dose: 7.14 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

Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.31 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 250712
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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