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- EMDB-37675: Cryo EM map of SLC7A10-SLC3A2 complex in the D-serine bound state -

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Basic information

Entry
Database: EMDB / ID: EMD-37675
TitleCryo EM map of SLC7A10-SLC3A2 complex in the D-serine bound state
Map datacryo EM map of SLC7A10-SLC3A2 complex in the D-serine bound state
Sample
  • Complex: 4F2hc-ASC-1 complex
    • Protein or peptide: Amino acid transporter heavy chain SLC3A2
    • Protein or peptide: Asc-type amino acid transporter 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: D-SERINESerine
KeywordsSLC7A10 / SLC3A2 / 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) / methionine transport / tyrosine transport / L-histidine transport ...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) / 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 / negative regulation of brown fat cell differentiation / L-leucine transmembrane transporter activity / proline transport / amino acid transmembrane transport / calcium:sodium antiporter activity / L-leucine transport / thyroid hormone transport / neutral amino acid 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 / 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
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: 3.5 Å
AuthorsLi YN / Guo YY / Dai L / Yan RH
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2024
Title: Cryo-EM structure of the human Asc-1 transporter complex.
Authors: Yaning Li / Yingying Guo / Angelika Bröer / Lu Dai / Stefan Brӧer / Renhong Yan /
Abstract: The Alanine-Serine-Cysteine transporter 1 (Asc-1 or SLC7A10) forms a crucial heterodimeric transporter complex with 4F2hc (SLC3A2) through a covalent disulfide bridge. This complex enables the sodium- ...The Alanine-Serine-Cysteine transporter 1 (Asc-1 or SLC7A10) forms a crucial heterodimeric transporter complex with 4F2hc (SLC3A2) through a covalent disulfide bridge. This complex enables the sodium-independent transport of small neutral amino acids, including L-Alanine (L-Ala), Glycine (Gly), and D-Serine (D-Ser), within the central nervous system (CNS). D-Ser and Gly are two key endogenous glutamate co-agonists that activate N-methyl-d-aspartate (NMDA) receptors by binding to the allosteric site. Mice deficient in Asc-1 display severe symptoms such as tremors, ataxia, and seizures, leading to early postnatal death. Despite its physiological importance, the functional mechanism of the Asc-1-4F2hc complex has remained elusive. Here, we present cryo-electron microscopy (cryo-EM) structures of the human Asc-1-4F2hc complex in its apo state, D-Ser bound state, and L-Ala bound state, resolved at 3.6 Å, 3.5 Å, and 3.4 Å, respectively. Through detailed structural analysis and transport assays, we uncover a comprehensive alternating access mechanism that underlies conformational changes in the complex. In summary, our findings reveal the architecture of the Asc-1 and 4F2hc complex and provide valuable insights into substrate recognition and the functional cycle of this essential transporter complex.
History
DepositionOct 6, 2023-
Header (metadata) releaseMay 15, 2024-
Map releaseMay 15, 2024-
UpdateMay 15, 2024-
Current statusMay 15, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_37675.png

Downloads & links

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Map

FileDownload / File: emd_37675.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcryo EM map of SLC7A10-SLC3A2 complex in the D-serine bound state
Voxel sizeX=Y=Z: 1.095 Å
Density
Contour LevelBy AUTHOR: 0.55
Minimum - Maximum-3.3558025 - 5.2298265
Average (Standard dev.)-0.0019044803 (±0.076685764)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 280.32 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: cryo EM half map of SLC7A10-SLC3A2 complex in...

Fileemd_37675_half_map_1.map
Annotationcryo EM half map of SLC7A10-SLC3A2 complex in the D-serine bound state
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: cryo EM half map of SLC7A10-SLC3A2 complex in...

Fileemd_37675_half_map_2.map
Annotationcryo EM half map of SLC7A10-SLC3A2 complex in the D-serine bound state
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : 4F2hc-ASC-1 complex

EntireName: 4F2hc-ASC-1 complex
Components
  • Complex: 4F2hc-ASC-1 complex
    • Protein or peptide: Amino acid transporter heavy chain SLC3A2
    • Protein or peptide: Asc-type amino acid transporter 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: D-SERINESerine

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Supramolecule #1: 4F2hc-ASC-1 complex

SupramoleculeName: 4F2hc-ASC-1 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Amino acid transporter heavy chain SLC3A2

MacromoleculeName: Amino acid transporter heavy chain SLC3A2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 68.16468 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MELQPPEASI AVVSIPRQLP GSHSEAGVQG LSAGDDSETG SDCVTQAGLQ LLASSDPPAL ASKNAEVTVE TGFHHVSQAD IEFLTSIDP TASASGSAGI TGTMSQDTEV DMKEVELNEL EPEKQPMNAA SGAAMSLAGA EKNGLVKIKV AEDEAEAAAA A KFTGLSKE ...String:
MELQPPEASI AVVSIPRQLP GSHSEAGVQG LSAGDDSETG SDCVTQAGLQ LLASSDPPAL ASKNAEVTVE TGFHHVSQAD IEFLTSIDP TASASGSAGI 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 #2: Asc-type amino acid transporter 1

MacromoleculeName: Asc-type amino acid transporter 1 / type: protein_or_peptide / ID: 2 / 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 #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 4 / 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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Macromolecule #4: D-SERINE

MacromoleculeName: D-SERINE / type: ligand / ID: 4 / Number of copies: 1 / Formula: DSN
Molecular weightTheoretical: 105.093 Da
Chemical component information

ChemComp-DSN:
D-SERINE / Serine

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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: 7.5
VitrificationCryogen name: ETHANE

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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 / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.2 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / 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: NONE
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 300000

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