9CJK
Human TMED9 octamer structure
Summary for 9CJK
| Entry DOI | 10.2210/pdb9cjk/pdb |
| EMDB information | 45634 |
| Descriptor | Transmembrane emp24 domain-containing protein 9, [(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 (2 entities in total) |
| Functional Keywords | tmed9, misfolded protein, secretory pathway, protein transport |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 8 |
| Total formula weight | 219538.23 |
| Authors | |
| Primary citation | Xiao, L.,Pi, X.,Goss, A.C.,El-Baba, T.,Ehrmann, J.F.,Grinkevich, E.,Bazua-Valenti, S.,Padovano, V.,Alper, S.L.,Carey, D.,Udeshi, N.D.,Carr, S.A.,Pablo, J.L.,Robinson, C.V.,Greka, A.,Wu, H. Molecular basis of TMED9 oligomerization and entrapment of misfolded protein cargo in the early secretory pathway. Sci Adv, 10:eadp2221-eadp2221, 2024 Cited by PubMed 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. PubMed: 39303030DOI: 10.1126/sciadv.adp2221 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.7 Å) |
Structure validation
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