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- EMDB-48638: Structure of Human SLC33A1 in complex with oxidized glutathione -

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Basic information

Entry
Database: EMDB / ID: EMD-48638
TitleStructure of Human SLC33A1 in complex with oxidized glutathione
Map dataDensity modified map for coordinate refinement
Sample
  • Organelle or cellular component: Human SLC33A1 with MAP tag insertion
    • Protein or peptide: Acetyl-coenzyme A transporter 1
  • Ligand: OXIDIZED GLUTATHIONE DISULFIDE
KeywordsGlutathione / TRANSPORT PROTEIN
Function / homology
Function and homology information


acetyl-CoA transmembrane transporter activity / acetyl-CoA transmembrane transport / Transport of vitamins, nucleosides, and related molecules / Defective SLC33A1 causes spastic paraplegia 42 (SPG42) / transmembrane transport / Golgi membrane / endoplasmic reticulum membrane / protein homodimerization activity / membrane / plasma membrane
Similarity search - Function
Acetyl-coenzyme A transporter 1-like / Acetyl-coenzyme A transporter 1 / AmpG-like permease/Acetyl-coenzyme A transporter 1 / MFS transporter superfamily
Similarity search - Domain/homology
Acetyl-coenzyme A transporter 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.26 Å
AuthorsGad M / Hite RK
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: Nat Cell Biol / Year: 2026
Title: SLC33A1 exports oxidized glutathione to maintain endoplasmic reticulum redox homeostasis.
Authors: Shanshan Liu / Mark Gad / Caifan Li / Kevin Cho / Yuyang Liu / Khando Wangdu / Viktor Belay / Alon Millet / Hiroyuki Kojima / Henry Sanford / Michele Wölk / Linas Urnavicius / Maria ...Authors: Shanshan Liu / Mark Gad / Caifan Li / Kevin Cho / Yuyang Liu / Khando Wangdu / Viktor Belay / Alon Millet / Hiroyuki Kojima / Henry Sanford / Michele Wölk / Linas Urnavicius / Maria Fedorova / Gary J Patti / Ekaterina V Vinogradova / Richard K Hite / Kıvanç Birsoy /
Abstract: The endoplasmic reticulum (ER) requires an oxidative environment to support the efficient maturation of secretory and membrane proteins. This is in part established by glutathione, a redox-active ...The endoplasmic reticulum (ER) requires an oxidative environment to support the efficient maturation of secretory and membrane proteins. This is in part established by glutathione, a redox-active metabolite present in reduced (GSH) and oxidized (GSSG) forms. The ER maintains a higher GSSG:GSH ratio than the cytosol; however, the mechanisms controlling ER redox balance remain poorly understood. To address this, we developed a method for the rapid immunopurification of the ER, enabling comprehensive profiling of its proteome and metabolome. Combining this approach with CRISPR screening, we identified SLC33A1 as the major ER GSSG exporter in mammalian cells. Loss of SLC33A1 led to GSSG accumulation in the ER and a liposome-based assay demonstrated that SLC33A1 directly transports GSSG. Cryogenic electron microscopy structures and molecular dynamics simulations revealed how SLC33A1 binds GSSG and identified residues critical for its transport. Finally, an imbalance in GSSG:GSH ratio induced ER stress and dependency on the ER-associated degradation pathway, driven by a shift in protein disulfide isomerases towards their oxidized forms. Together, our work establishes SLC33A1-mediated GSSG export as a key mechanism for ER redox homeostasis and protein maturation.
History
DepositionJan 14, 2025-
Header (metadata) releaseFeb 25, 2026-
Map releaseFeb 25, 2026-
UpdateMay 27, 2026-
Current statusMay 27, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48638.png

Downloads & links

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Map

FileDownload / File: emd_48638.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationDensity modified map for coordinate refinement
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.73 Å/pix.
x 384 pix.
= 278.4 Å		0.73 Å/pix.
x 384 pix.
= 278.4 Å		0.73 Å/pix.
x 384 pix.
= 278.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.725 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 2.0
Minimum - Maximum-18.703434000000001 - 28.425650000000001
Average (Standard dev.)-0.0000026105695 (±0.32750064)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 278.40002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map 1

Fileemd_48638_half_map_1.map
AnnotationHalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map 2

Fileemd_48638_half_map_2.map
AnnotationHalf Map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human SLC33A1 with MAP tag insertion

EntireName: Human SLC33A1 with MAP tag insertion
Components
  • Organelle or cellular component: Human SLC33A1 with MAP tag insertion
    • Protein or peptide: Acetyl-coenzyme A transporter 1
  • Ligand: OXIDIZED GLUTATHIONE DISULFIDE

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Supramolecule #1: Human SLC33A1 with MAP tag insertion

SupramoleculeName: Human SLC33A1 with MAP tag insertion / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 62 KDa

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Macromolecule #1: Acetyl-coenzyme A transporter 1

MacromoleculeName: Acetyl-coenzyme A transporter 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 62.159895 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSPTISHKDS SRQRRPGNFS HSLDMKSGPL PPGGWDDSHL DSAGREGDRE ALLGDTGTGD FLKAPQSFRA ELSSILLLLF LYVLQGIPL GLAGSIPLIL QSKNVSYTDQ AFFSFVFWPF SLKLLWAPLV DAVYVKNFGR RKSWLVPTQY ILGLFMIYLS T QVDRLLGN ...String:
MSPTISHKDS SRQRRPGNFS HSLDMKSGPL PPGGWDDSHL DSAGREGDRE ALLGDTGTGD FLKAPQSFRA ELSSILLLLF LYVLQGIPL GLAGSIPLIL QSKNVSYTDQ AFFSFVFWPF SLKLLWAPLV DAVYVKNFGR RKSWLVPTQY ILGLFMIYLS T QVDRLLGN TDDRTPDVIA LTVAFFLFEF LAATQDIAVD GWALTMLSRE NVGYASTCNS VGQTAGYFLG NVLFLALESA DF CNKYLRF QPQPRGIVTL SDFLFFWGTV FLITTTLVAL LKKENEVSVV KEETQGITDT YKLLFAIIKM PAVLTFCLLI LTA KIGFSA ADAVTGLKLV EEGVPKEHLA LLAVPMVPLQ IILPLIISKY TAGPQPLNTF YKAMPYRLLL GLEYALLVWW TPKV EGDGM VPPGPIYYYI VVLLSYALHQ VTVYSMYVSI MAFNAKVSDP LIGGTYMTLL NTVSNLGGNW PSTVALWLVD PLTVK ECVG ASNQNCRTPD AVELCKKLGG SCVTALDGYY VESIICVFIG FGWWFFLGPK FKKLQDEGSS SWKCKRNNSN SLEVLF Q

UniProtKB: Acetyl-coenzyme A transporter 1

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Macromolecule #2: OXIDIZED GLUTATHIONE DISULFIDE

MacromoleculeName: OXIDIZED GLUTATHIONE DISULFIDE / type: ligand / ID: 2 / Number of copies: 1 / Formula: GDS
Molecular weightTheoretical: 612.631 Da
Chemical component information

ChemComp-GDS:
OXIDIZED GLUTATHIONE DISULFIDE

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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

Concentration5 mg/mL
BufferpH: 7.4
Component:
ConcentrationNameFormula
20.0 mMHepes
150.0 mMpotassium chlorideKCl
0.01 percentLMNG
0.001 percentCHS
18.0 micromolarGDN
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 297 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DARK FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.26 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 215071
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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