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- EMDB-18379: Structure of human Asc1/CD98hc heteromeric amino acid transporter -

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Basic information

Entry
Database: EMDB / ID: EMD-18379
TitleStructure of human Asc1/CD98hc heteromeric amino acid transporter
Map data
Sample
  • Complex: Asc1/CD98hc
    • Protein or peptide: Asc-type amino acid transporter 1
    • Protein or peptide: 4F2 cell-surface antigen heavy chain
  • Ligand: Digitonin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsHeteromeric amino acid transporter Transporter APC transporter / MEMBRANE PROTEIN
Function / homology
Function and homology information


D-alanine transmembrane transport / D-serine transmembrane transport / positive regulation of synaptic transmission, glycinergic / glycine transport / L-serine 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 ...D-alanine transmembrane transport / D-serine transmembrane transport / positive regulation of synaptic transmission, glycinergic / glycine transport / L-serine 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 / negative regulation of brown fat cell differentiation / 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 / neutral amino acid 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 / 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 / Asc-type amino acid transporter 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.0 Å
AuthorsMartinez-Molledo M / Rullo-Tubau J / Errasti-Murugarren E / Palacin M / Llorca O
Funding support Spain, 1 items
OrganizationGrant numberCountry
La Caixa FoundationLCF/PR/HR20/52400017 Spain
CitationJournal: Nat Commun / Year: 2024
Title: Structure and mechanisms of transport of human Asc1/CD98hc amino acid transporter.
Authors: Josep Rullo-Tubau / Maria Martinez-Molledo / Paola Bartoccioni / Ignasi Puch-Giner / Ángela Arias / Suwipa Saen-Oon / Camille Stephan-Otto Attolini / Rafael Artuch / Lucía Díaz / Víctor ...Authors: Josep Rullo-Tubau / Maria Martinez-Molledo / Paola Bartoccioni / Ignasi Puch-Giner / Ángela Arias / Suwipa Saen-Oon / Camille Stephan-Otto Attolini / Rafael Artuch / Lucía Díaz / Víctor Guallar / Ekaitz Errasti-Murugarren / Manuel Palacín / Oscar Llorca /
Abstract: Recent cryoEM studies elucidated details of the structural basis for the substrate selectivity and translocation of heteromeric amino acid transporters. However, Asc1/CD98hc is the only neutral ...Recent cryoEM studies elucidated details of the structural basis for the substrate selectivity and translocation of heteromeric amino acid transporters. However, Asc1/CD98hc is the only neutral heteromeric amino acid transporter that can function through facilitated diffusion, and the only one that efficiently transports glycine and D-serine, and thus has a regulatory role in the central nervous system. Here we use cryoEM, ligand-binding simulations, mutagenesis, transport assays, and molecular dynamics to define human Asc1/CD98hc determinants for substrate specificity and gain insights into the mechanisms that govern substrate translocation by exchange and facilitated diffusion. The cryoEM structure of Asc1/CD98hc is determined at 3.4-3.8 Å resolution, revealing an inward-facing semi-occluded conformation. We find that Ser 246 and Tyr 333 are essential for Asc1/CD98hc substrate selectivity and for the exchange and facilitated diffusion modes of transport. Taken together, these results reveal the structural bases for ligand binding and transport features specific to human Asc1.
History
DepositionSep 1, 2023-
Header (metadata) releaseApr 10, 2024-
Map releaseApr 10, 2024-
UpdateApr 17, 2024-
Current statusApr 17, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_18379.png

Downloads & links

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Map

FileDownload / File: emd_18379.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.831 Å
Density
Contour LevelBy AUTHOR: 0.01
Minimum - Maximum-0.054749534 - 0.08602518
Average (Standard dev.)0.00000067040685 (±0.0014132812)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 249.29999 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_18379_additional_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_18379_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_18379_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Asc1/CD98hc

EntireName: Asc1/CD98hc
Components
  • Complex: Asc1/CD98hc
    • Protein or peptide: Asc-type amino acid transporter 1
    • Protein or peptide: 4F2 cell-surface antigen heavy chain
  • Ligand: Digitonin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Asc1/CD98hc

SupramoleculeName: Asc1/CD98hc / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Asc-type amino acid transporter 1

MacromoleculeName: Asc-type amino acid transporter 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 56.837504 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAGHTQQPSG RGNPRPAPSP SPVPGTVPGA SERVALKKEI GLLSACTIII GNIIGSGIFI SPKGVLEHSG SVGLALFVWV LGGGVTALG SLCYAELGVA IPKSGGDYAY VTEIFGGLAG FLLLWSAVLI MYPTSLAVIS MTFSNYVLQP VFPNCIPPTT A SRVLSMAC ...String:
MAGHTQQPSG RGNPRPAPSP SPVPGTVPGA SERVALKKEI GLLSACTIII GNIIGSGIFI SPKGVLEHSG SVGLALFVWV LGGGVTALG SLCYAELGVA IPKSGGDYAY VTEIFGGLAG FLLLWSAVLI MYPTSLAVIS MTFSNYVLQP VFPNCIPPTT A SRVLSMAC LMLLTWVNSS SVRWATRIQD MFTGGKLLAL SLIIGVGLLQ IFQGHFEELR PSNAFAFWMT PSVGHLALAF LQ GSFAFSG WNFLNYVTEE MVDARKNLPR AIFISIPLVT FVYTFTNIAY FTAMSPQELL SSNAVAVTFG EKLLGYFSWV MPV SVALST FGGINGYLFT YSRLCFSGAR EGHLPSLLAM IHVRHCTPIP ALLVCCGATA VIMLVGDTYT LINYVSFINY LCYG VTILG LLLLRWRRPA LHRPIKVNLL IPVAYLVFWA FLLVFSFISE PMVCGVGVII ILTGVPIFFL GVFWRSKPKC VHRLT ESMT HWGQELCFVV YPQDAPEEEE NGPCPPSLLP ATDKPSKPQ

UniProtKB: Asc-type amino acid transporter 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: 68.056688 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MELQPPEASI AVVSIPRQLP GSHSEAGVQG LSAGDDSELG SHCVAQTGLE LLASGDPLPS ASQNAEMIET GSDCVTQAGL QLLASSDPP ALASKNAEVT GTMSQDTEVD MKEVELNELE PEKQPMNAAS GAAMSLAGAE KNGLVKIKVA EDEAEAAAAA K FTGLSKEE ...String:
MELQPPEASI AVVSIPRQLP GSHSEAGVQG LSAGDDSELG SHCVAQTGLE LLASGDPLPS ASQNAEMIET GSDCVTQAGL QLLASSDPP ALASKNAEVT GTMSQDTEVD MKEVELNELE PEKQPMNAAS GAAMSLAGAE KNGLVKIKVA EDEAEAAAAA K FTGLSKEE LLKVAGSPGW VRTRWALLLL FWLGWLGMLA GAVVIIVRAP RCRELPAQKW WHTGALYRIG DLQAFQGHGA GN LAGLKGR LDYLSSLKVK GLVLGPIHKN QKDDVAQTDL LQIDPNFGSK EDFDSLLQSA KKKSIRVILD LTPNYRGENS WFS TQVDTV ATKVKDALEF WLQAGVDGFQ VRDIENLKDA SSFLAEWQNI TKGFSEDRLL IAGTNSSDLQ QILSLLESNK DLLL TSSYL SDSGSTGEHT KSLVTQYLNA TGNRWCSWSL SQARLLTSFL PAQLLRLYQL MLFTLPGTPV FSYGDEIGLD AAALP GQPM EAPVMLWDES SFPDIPGAVS ANMTVKGQSE DPGSLLSLFR RLSDQRSKER SLLHGDFHAF SAGPGLFSYI RHWDQN ERF LVVLNFGDVG LSAGLQASDL PASASLPAKA DLLLSTQPGR EEGSPLELER LKLEPHEGLL LRFPYAA

UniProtKB: Amino acid transporter heavy chain SLC3A2

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Macromolecule #5: Digitonin

MacromoleculeName: Digitonin / type: ligand / ID: 5 / Number of copies: 1 / Formula: AJP
Molecular weightTheoretical: 1.229312 KDa
Chemical component information

ChemComp-AJP:
Digitonin / detergent*YM / Digitonin

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 1 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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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

Concentration1.2 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
20.0 mMTris-HClTrisTris hydrochloride
150.0 mMNaClSodium chlorideSodium chloride
0.1 %dgtDigitonin
GridModel: Quantifoil R0.6/1 / Material: COPPER / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE-PROPANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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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 / Cs: 2.7 mm / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number real images: 31696 / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: AlphaFold
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 139507

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