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

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
,
et al

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.

Keywords:

Golgi Apparatus

,

Humans

,

Membrane Proteins

,

Coat Protein Complex I

,

Cryoelectron Microscopy

,

Protein Binding

,

Protein Folding

,

Protein Transport

,

Models, Molecular

,

Protein Multimerization

,

Secretory Pathway

,

Protein Domains