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- EMDB-45634: Human TMED9 octamer structure -

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Basic information

Entry
Database: EMDB / ID: EMD-45634
TitleHuman TMED9 octamer structure
Map dataHuman TMED9 octamer structure
Sample
  • Complex: TMED9 octamer
    • Protein or peptide: Transmembrane emp24 domain-containing protein 9
  • Ligand: [(2R)-2-[(E)-octadec-9-enoyl]oxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] (E)-octadec-9-enoate
Keywordstmed9 / misfolded protein / secretory pathway / PROTEIN TRANSPORT
Function / homology
Function and homology information


COPI coating of Golgi vesicle / positive regulation of organelle organization / trans-Golgi network transport vesicle / syntaxin binding / COPI-dependent Golgi-to-ER retrograde traffic / COPII-coated ER to Golgi transport vesicle / Golgi organization / endoplasmic reticulum-Golgi intermediate compartment / endoplasmic reticulum to Golgi vesicle-mediated transport / COPI-mediated anterograde transport ...COPI coating of Golgi vesicle / positive regulation of organelle organization / trans-Golgi network transport vesicle / syntaxin binding / COPI-dependent Golgi-to-ER retrograde traffic / COPII-coated ER to Golgi transport vesicle / Golgi organization / endoplasmic reticulum-Golgi intermediate compartment / endoplasmic reticulum to Golgi vesicle-mediated transport / COPI-mediated anterograde transport / transport vesicle / endoplasmic reticulum-Golgi intermediate compartment membrane / intracellular protein transport / synaptic vesicle / Golgi membrane / endoplasmic reticulum membrane / endoplasmic reticulum / Golgi apparatus / extracellular exosome
Similarity search - Function
Transmembrane emp24 domain-containing protein / emp24/gp25L/p24 family/GOLD / emp24/gp25L/p24 family/GOLD / GOLD domain / GOLD domain profile.
Similarity search - Domain/homology
Transmembrane emp24 domain-containing protein 9
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsLe X / Xiong P
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: Sci Adv / Year: 2024
Title: Molecular basis of TMED9 oligomerization and entrapment of misfolded protein cargo in the early secretory pathway.
Authors: Le Xiao / Xiong Pi / Alissa C Goss / Tarick El-Baba / Julian F Ehrmann / Elizabeth Grinkevich / Silvana Bazua-Valenti / Valeria Padovano / Seth L Alper / Dominique Carey / Namrata D Udeshi / ...Authors: Le Xiao / Xiong Pi / Alissa C Goss / Tarick El-Baba / Julian F Ehrmann / Elizabeth Grinkevich / Silvana Bazua-Valenti / Valeria Padovano / Seth L Alper / Dominique Carey / Namrata D Udeshi / Steven A Carr / Juan Lorenzo Pablo / Carol V Robinson / Anna Greka / Hao Wu /
Abstract: Intracellular accumulation of misfolded proteins causes serious human proteinopathies. The transmembrane emp24 domain 9 (TMED9) cargo receptor promotes a general mechanism of cytotoxicity by ...Intracellular accumulation of misfolded proteins causes serious human proteinopathies. The transmembrane emp24 domain 9 (TMED9) cargo receptor promotes a general mechanism of cytotoxicity by entrapping misfolded protein cargos in the early secretory pathway. However, the molecular basis for this TMED9-mediated cargo retention remains elusive. Here, we report cryo-electron microscopy structures of TMED9, which reveal its unexpected self-oligomerization into octamers, dodecamers, and, by extension, even higher-order oligomers. The TMED9 oligomerization is driven by an intrinsic symmetry mismatch between the trimeric coiled coil domain and the tetrameric transmembrane domain. Using frameshifted Mucin 1 as an example of aggregated disease-related protein cargo, we implicate a mode of direct interaction with the TMED9 luminal Golgi-dynamics domain. The structures suggest and we confirm that TMED9 oligomerization favors the recruitment of coat protein I (COPI), but not COPII coatomers, facilitating retrograde transport and explaining the observed cargo entrapment. Our work thus reveals a molecular basis for TMED9-mediated misfolded protein retention in the early secretory pathway.
History
DepositionJul 6, 2024-
Header (metadata) releaseOct 2, 2024-
Map releaseOct 2, 2024-
UpdateOct 2, 2024-
Current statusOct 2, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45634.png

Downloads & links

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Map

FileDownload / File: emd_45634.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman TMED9 octamer structure
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 320 pix.
= 264. Å		0.83 Å/pix.
x 320 pix.
= 264. Å		0.83 Å/pix.
x 320 pix.
= 264. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.025
Minimum - Maximum-0.1411096 - 0.18280125
Average (Standard dev.)0.00007665469 (±0.002408249)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 264.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map A

Fileemd_45634_half_map_1.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map B

Fileemd_45634_half_map_2.map
AnnotationHalf Map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : TMED9 octamer

EntireName: TMED9 octamer
Components
  • Complex: TMED9 octamer
    • Protein or peptide: Transmembrane emp24 domain-containing protein 9
  • Ligand: [(2R)-2-[(E)-octadec-9-enoyl]oxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] (E)-octadec-9-enoate

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Supramolecule #1: TMED9 octamer

SupramoleculeName: TMED9 octamer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Transmembrane emp24 domain-containing protein 9

MacromoleculeName: Transmembrane emp24 domain-containing protein 9 / type: protein_or_peptide / ID: 1 / Number of copies: 8 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 27.314395 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAVELGVLLV RPRPGTGLGR VMRTLLLVLW LATRGSALYF HIGETEKKCF IEEIPDETMV IGNYRTQLYD KQREEYQPAT PGLGMFVEV KDPEDKVILA RQYGSEGRFT FTSHTPGEHQ ICLHSNSTKF SLFAGGMLRV HLDIQVGEHA NDYAEIAAKD K LSELQLRV ...String:
MAVELGVLLV RPRPGTGLGR VMRTLLLVLW LATRGSALYF HIGETEKKCF IEEIPDETMV IGNYRTQLYD KQREEYQPAT PGLGMFVEV KDPEDKVILA RQYGSEGRFT FTSHTPGEHQ ICLHSNSTKF SLFAGGMLRV HLDIQVGEHA NDYAEIAAKD K LSELQLRV RQLVEQVEQI QKEQNYQRWR EERFRQTSES TNQRVLWWSI LQTLILVAIG VWQMRHLKSF FEAKKLV

UniProtKB: Transmembrane emp24 domain-containing protein 9

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Macromolecule #2: [(2R)-2-[(E)-octadec-9-enoyl]oxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)...

MacromoleculeName: [(2R)-2-[(E)-octadec-9-enoyl]oxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] (E)-octadec-9-enoate
type: ligand / ID: 2 / Number of copies: 1 / Formula: 9ED
Molecular weightTheoretical: 1.023066 KDa

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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 TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 43.2 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 233493
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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