Molecular basis of TMED9 oligomerization and entrapment of misfolded protein cargo in the early secretory pathway
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.
Authors
- Carol V. Robinson (ORCID: https://orcid.org/0000-0001-7829-5505)
- Julian F. Ehrmann (ORCID: https://orcid.org/0000-0003-2518-5681)
- Seth L. Alper (ORCID: https://orcid.org/0000-0002-6228-2512)
- Hao Wu (ORCID: https://orcid.org/0000-0002-7281-8579)
- Silvana Bazúa‐Valenti (ORCID: https://orcid.org/0000-0001-8907-3852)
- Tarick J. El‐Baba (ORCID: https://orcid.org/0000-0003-4497-9938)
- Namrata D. Udeshi (ORCID: https://orcid.org/0000-0001-5312-1402)
- Elizabeth Grinkevich (ORCID: https://orcid.org/0000-0001-6834-2558)
- Valeria Padovano (ORCID: https://orcid.org/0000-0002-0142-3385)
- Steven A. Carr (ORCID: https://orcid.org/0000-0002-7203-4299)
- Anna Greka (ORCID: https://orcid.org/0000-0001-5697-7791)
- Xiong Pi (ORCID: https://orcid.org/0000-0001-8835-6914)
- Juan Lorenzo Pablo (ORCID: https://orcid.org/0000-0002-0804-9074)
- Le Xiao (ORCID: https://orcid.org/0000-0003-2512-3990)
- Dominique K. Carey
- Alissa C. Goss
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- University of Oxford (GB)
Publication Details
- Journal
- Science Advances
- Published
- 2024-09-20
- DOI
- https://doi.org/10.1126/sciadv.adp2221
- Citations
- 9
- Primary Topic
- Cellular transport and secretion
- Type
- article
- Field-Weighted Citation Impact
- 2.93
Funders
- Cancer Research Institute
- American Society of Nephrology
- Broad Institute