MassIVE MSV000089757

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Molecular basis of TMED9 oligomerization and entrapment of misfolded protein cargo in the early secretory pathway

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Description

Xiao L, Pi X, Goss AC, El-Baba T, Ehrmann JF, Grinkevich E, Bazua-Valenti S, Padovano V, Alper SL, Carey D, Udeshi ND, Carr SA, Pablo JL, Robinson CV, Greka A, Wu H. 2024 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 cargoes in the early secretory pathway. However, the molecular basis for this TMED9-mediated cargo retention remains elusive. Here we report cryoEM 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 (GOLD) domain. The structures suggest and we confirm that TMED9 oligomerization favors the recruitment of 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. [doi:10.25345/C5ZW18W9V] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: TMT ; membrane

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Principal Investigators:
(in alphabetical order) 		Steven A. Carr, Broad Institute of MIT and Harvard, United States
Submitting User: clauser
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