+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-9849 | |||||||||
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Title | LAT1-CD98hc complex bound to MEM-108 Fab | |||||||||
Map data | Sharpened, masked map | |||||||||
Sample |
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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 / amino acid import across plasma membrane / thyroid hormone transmembrane transporter activity / neutral L-amino acid secondary active transmembrane transporter activity / Defective SLC7A7 causes lysinuric protein intolerance (LPI) / tyrosine 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 / amino acid import across plasma membrane / thyroid hormone transmembrane transporter activity / 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 / L-amino acid transmembrane transporter activity / 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 / amino acid transmembrane transport / calcium:sodium antiporter activity / neutral amino acid transport / positive regulation of cytokine production involved in immune response / L-leucine transport / thyroid hormone transport / amino acid transmembrane transporter activity / negative regulation of vascular associated smooth muscle cell apoptotic process / Amino acid transport across the plasma membrane / neutral L-amino acid transmembrane transporter activity / external side of apical plasma membrane / Tryptophan catabolism / exogenous protein binding / amino acid transport / xenobiotic transport / anchoring junction / antiporter activity / response to muscle activity / Basigin interactions / microvillus membrane / response to exogenous dsRNA / positive regulation of interleukin-17 production / tryptophan transport / transport across blood-brain barrier / positive regulation of interleukin-4 production / 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 / calcium ion transport / melanosome / positive regulation of type II interferon production / double-stranded RNA binding / virus receptor activity / basolateral plasma membrane / cellular response to lipopolysaccharide / carbohydrate metabolic process / cadherin binding / symbiont entry into host cell / apical plasma membrane / protein heterodimerization activity / 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 | |||||||||
Biological species | Homo sapiens (human) / Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.31 Å | |||||||||
Authors | Lee Y / Nishizawa T / Kusakizako T / Oda K / Ishitani R / Nakane T / Nureki O | |||||||||
Funding support | Japan, 2 items
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Citation | Journal: 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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_9849.map.gz | 5.5 MB | EMDB map data format | |
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Header (meta data) | emd-9849-v30.xml emd-9849.xml | 21.9 KB 21.9 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_9849_fsc.xml | 10.2 KB | Display | FSC data file |
Images | emd_9849.png | 94.1 KB | ||
Masks | emd_9849_msk_1.map | 91.1 MB | Mask map | |
Others | emd_9849_half_map_1.map.gz emd_9849_half_map_2.map.gz | 71.3 MB 71.2 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-9849 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-9849 | HTTPS FTP |
-Related structure data
Related structure data | 6jmqMC 9850C 6jmrC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | |
EM raw data | EMPIAR-10264 (Title: LAT1-CD98hc bound to MEM-108 Fab / Data size: 4.1 TB Data #1: Unaligned multi-frame micrographs, Dataset1 [micrographs - multiframe] Data #2: Unaligned multi-frame micrographs, Dataset2 [micrographs - multiframe] Data #3: Micelle subtracted particles used for final reconstruction [picked particles - single frame - processed]) |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_9849.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | Sharpened, masked map | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.333 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
File | emd_9849_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: Half map 2 used for FSC calculation. The...
File | emd_9849_half_map_1.map | ||||||||||||
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Annotation | Half 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 |
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Density Histograms |
-Half map: Half map 1 used for FSC calculation. The...
File | emd_9849_half_map_2.map | ||||||||||||
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Annotation | Half 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 |
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Density Histograms |
-Sample components
-Entire : LAT1-CD98hc complex bound to MEM-108 Fab
Entire | Name: LAT1-CD98hc complex bound to MEM-108 Fab |
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Components |
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-Supramolecule #1: LAT1-CD98hc complex bound to MEM-108 Fab
Supramolecule | Name: LAT1-CD98hc complex bound to MEM-108 Fab / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4 |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Experimental: 175 kDa/nm |
-Macromolecule #1: Large neutral amino acids transporter small subunit 1
Macromolecule | Name: Large neutral amino acids transporter small subunit 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 56.043746 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: 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 |
-Macromolecule #2: 4F2 cell-surface antigen heavy chain
Macromolecule | Name: 4F2 cell-surface antigen heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 68.069625 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: 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 |
-Macromolecule #3: Antibody
Macromolecule | Name: Antibody / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 22.577857 KDa |
Recombinant expression | Organism: Mus musculus (house mouse) |
Sequence | 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 ...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 |
-Macromolecule #4: Antibody
Macromolecule | Name: Antibody / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 23.227152 KDa |
Recombinant expression | Organism: Mus musculus (house mouse) |
Sequence | 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 ...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 |
-Macromolecule #5: CHOLESTEROL
Macromolecule | Name: CHOLESTEROL / type: ligand / ID: 5 / Number of copies: 5 / Formula: CLR |
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Molecular weight | Theoretical: 386.654 Da |
Chemical component information | ChemComp-CLR: |
-Macromolecule #6: N-ACETYL-D-GLUCOSAMINE
Macromolecule | Name: N-ACETYL-D-GLUCOSAMINE / type: ligand / ID: 6 / Number of copies: 5 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 8 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy |
Image recording | Film or detector model: FEI FALCON III (4k x 4k) / Average electron dose: 7.14 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |