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- EMDB-9850: CD98hc extracellular domain bound to HBJ127 Fab and MEM-108 Fab -

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Basic information

Entry
Database: EMDB / ID: EMD-9850
TitleCD98hc extracellular domain bound to HBJ127 Fab and MEM-108 Fab
Map dataMasked, sharpend map calculated with the mask covering CD98hc-ED and two Fabs.
Sample
  • Complex: CD98hc extracellular domain bound to MEM-108 Fab and HBJ127 Fab
    • Protein or peptide: Antibody
    • Protein or peptide: Antibody
    • Protein or peptide: 4F2 cell-surface antigen heavy chain
    • Protein or peptide: Antibody
    • Protein or peptide: Antibody
  • Ligand: N-ACETYL-D-GLUCOSAMINEN-Acetylglucosamine
Function / homology
Function and homology information


neutral L-amino acid secondary active transmembrane transporter activity / Defective SLC7A7 causes lysinuric protein intolerance (LPI) / tyrosine transport / L-histidine transport / apical pole of neuron / aromatic amino acid transmembrane transporter activity / amino acid transport complex / methionine transport / : / L-leucine import across plasma membrane ...neutral L-amino acid secondary active transmembrane transporter activity / Defective SLC7A7 causes lysinuric protein intolerance (LPI) / tyrosine transport / L-histidine transport / apical pole of neuron / aromatic amino acid transmembrane transporter activity / amino acid transport complex / methionine transport / : / 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 / proline transport / calcium:sodium antiporter activity / L-leucine transport / thyroid hormone transport / Amino acid transport across the plasma membrane / neutral L-amino acid transmembrane transporter activity / Tryptophan catabolism / exogenous protein binding / amino acid transport / anchoring junction / Basigin interactions / response to exogenous dsRNA / tryptophan transport / basal plasma membrane / calcium ion transport / melanosome / double-stranded RNA binding / 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
Solute carrier family 3 member 2, N-terminal domain / 4F2 cell-surface antigen heavy chain / Solute carrier family 3 member 2 N-terminus / 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
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.1 Å
AuthorsLee Y / Nishizawa T / Kusakizako T / Oda K / Ishitani R / Yokoyama T / Nakane T / Shirouzu M / Nureki O
Funding support Japan, 3 items
OrganizationGrant numberCountry
Japan Society for the Promotion of ScienceJP16J07405 Japan
Japan Agency for Medical Research and Development (AMED)JP18am0101115 Japan
Japan Agency for Medical Research and Development (AMED)JP18am0101082 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-
UpdateJun 19, 2019-
Current statusJun 19, 2019Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.035
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.035
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6jmr
  • Surface level: 0.035
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_9850.png

Downloads & links

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Map

FileDownload / File: emd_9850.map.gz / Format: CCP4 / Size: 26.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMasked, sharpend map calculated with the mask covering CD98hc-ED and two Fabs.
Voxel sizeX=Y=Z: 1.49 Å
Density
Contour LevelBy AUTHOR: 0.035 / Movie #1: 0.035
Minimum - Maximum-0.086455256 - 0.14439514
Average (Standard dev.)0.00019591463 (±0.0033973865)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions190190190
Spacing190190190
CellA=B=C: 283.1 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.491.491.49
M x/y/z190190190
origin x/y/z0.0000.0000.000
length x/y/z283.100283.100283.100
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ858858858
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS190190190
D min/max/mean-0.0860.1440.000

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Supplemental data

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Mask #1

Fileemd_9850_msk_1.map
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.

Fileemd_9850_half_map_1.map
AnnotationHalf map 1 used for FSC calculation.
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.

Fileemd_9850_half_map_2.map
AnnotationHalf map 2 used for FSC calculation.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : CD98hc extracellular domain bound to MEM-108 Fab and HBJ127 Fab

EntireName: CD98hc extracellular domain bound to MEM-108 Fab and HBJ127 Fab
Components
  • Complex: CD98hc extracellular domain bound to MEM-108 Fab and HBJ127 Fab
    • Protein or peptide: Antibody
    • Protein or peptide: Antibody
    • Protein or peptide: 4F2 cell-surface antigen heavy chain
    • Protein or peptide: Antibody
    • Protein or peptide: Antibody
  • Ligand: N-ACETYL-D-GLUCOSAMINEN-Acetylglucosamine

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Supramolecule #1: CD98hc extracellular domain bound to MEM-108 Fab and HBJ127 Fab

SupramoleculeName: CD98hc extracellular domain bound to MEM-108 Fab and HBJ127 Fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)
Molecular weightExperimental: 225 kDa/nm

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Macromolecule #1: Antibody

MacromoleculeName: Antibody / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.831834 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: QVKLLESGPG LVQPSQSLSI TCTVSGFSLT TYGIHWVRQP PGKGLEWLGV IWSNGRIDYN AAFISRLSIT KDNSKSQVFF KMNSLQDDD TAIYYCARNV YDSLTWFTYW GQGTLVTVSA AKTTPPSVYP LAPGSAAQTN SMVTLGCLVK GYFPEPVTVT W NSGSLSSG ...String:
QVKLLESGPG LVQPSQSLSI TCTVSGFSLT TYGIHWVRQP PGKGLEWLGV IWSNGRIDYN AAFISRLSIT KDNSKSQVFF KMNSLQDDD TAIYYCARNV YDSLTWFTYW GQGTLVTVSA AKTTPPSVYP LAPGSAAQTN SMVTLGCLVK GYFPEPVTVT W NSGSLSSG VHTFPAVLQS DLYTLSSSVT VPSSTWPSET VTCNVAHPAS STKVDKKIVP RD

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Macromolecule #2: Antibody

MacromoleculeName: Antibody / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.11467 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: DIQMTQSPSS LAVSVGEKVT MTCKSSQSLL YSSNQKNYLA WYQQKPGQSP KLLIFWASTR ESGVPDRFTG SGSGTDFPLT ISSVKAEDL AVYFCQQYTS YPTFGGGTKL EIKRADAAPT VSIFPPSSEQ LTSGGASVVC FLNNFYPKDI NVKWKIDGSE R QNGVLNSW ...String:
DIQMTQSPSS LAVSVGEKVT MTCKSSQSLL YSSNQKNYLA WYQQKPGQSP KLLIFWASTR ESGVPDRFTG SGSGTDFPLT ISSVKAEDL AVYFCQQYTS YPTFGGGTKL EIKRADAAPT VSIFPPSSEQ LTSGGASVVC FLNNFYPKDI NVKWKIDGSE R QNGVLNSW TDQDSKDSTY SMSSTLTLTK DEYERHNSYT CEATHKTSTS PIVKSFNRNE

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Macromolecule #3: 4F2 cell-surface antigen heavy chain

MacromoleculeName: 4F2 cell-surface antigen heavy chain / type: protein_or_peptide / ID: 3 / 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

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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: 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 #5: Antibody

MacromoleculeName: Antibody / type: protein_or_peptide / ID: 5 / 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: N-ACETYL-D-GLUCOSAMINE

MacromoleculeName: N-ACETYL-D-GLUCOSAMINE / type: ligand / ID: 6 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da

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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 TECNAI ARCTICA
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.2 e/Å2
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 160553
FSC plot (resolution estimation)

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