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- PDB-9cjl: Molecular basis of TMED9 dodecamer -

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Basic information

Entry
Database: PDB / ID: 9cjl
TitleMolecular basis of TMED9 dodecamer
ComponentsTransmembrane emp24 domain-containing protein 9
KeywordsPROTEIN TRANSPORT / tmed9 / misfolded protein / secretory pathway / Cryo-EM
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.5 Å
AuthorsLe, X. / Xiong, P.
Funding support United States, 1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 2, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transmembrane emp24 domain-containing protein 9
B: Transmembrane emp24 domain-containing protein 9
C: Transmembrane emp24 domain-containing protein 9
D: Transmembrane emp24 domain-containing protein 9
E: Transmembrane emp24 domain-containing protein 9
F: Transmembrane emp24 domain-containing protein 9
G: Transmembrane emp24 domain-containing protein 9
H: Transmembrane emp24 domain-containing protein 9
I: Transmembrane emp24 domain-containing protein 9
J: Transmembrane emp24 domain-containing protein 9
K: Transmembrane emp24 domain-containing protein 9
L: Transmembrane emp24 domain-containing protein 9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)329,81914
Polymers327,77312
Non-polymers2,0462
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Transmembrane emp24 domain-containing protein 9 / GMP25 / Glycoprotein 25L2 / p24 family protein alpha-2 / p24alpha2 / p25


Mass: 27314.395 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TMED9, GP25L2 / Production host: Homo sapiens (human) / References: UniProt: Q9BVK6
#2: Chemical ChemComp-9ED / [(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 / PtdIns(4,5)P2


Mass: 1023.066 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C45H85O19P3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: TMED9 dodecamer / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 43.2 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.19.2_4158: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 5.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 198652 / Symmetry type: POINT

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