ArticleScience advances2024
Molecular basis of TMED9 oligomerization and entrapment of misfolded protein cargo in the early secretory pathway.
Article in Science advances, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- The ER-Golgi intermediate compartment: a central hub integrating membrane trafficking and stress responses.EMBO reports · 2026Review
- A cargo receptor entrapment complex is a therapeutic node for genetically and clinically distinct proteinopathies.bioRxiv : the preprint server for biology · 2026Article
- IRE1-XBP1driven induction of TMED9 stabilizes ATF6 during ER stress to promote cell survival.Cellular & molecular biology letters · 2026Article
- Clinically distinct genetic diseases converge on shared, druggable nodes.Nature medicine · 2026Article
- Beyond Vesicular Traffic: The ERES as the Gateway for Biosynthetic Secretion.Sub-cellular biochemistry · 2026Review
- Article
- TMED9 coordinates the clearance of misfolded GPI-anchored proteins out of the ER and into the Golgi.PLoS biology · 2025Article
- Review
- TMED9: a potential therapeutic target and prognostic marker in glioma and its implications across pan-cancer contexts.Frontiers in immunology · 2025Article
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Authors and funding
16 authors.
Funding
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 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.
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Registered trials
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