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Human TMED9 octamer structure
Structural highlights
FunctionTMED9_HUMAN Appears to be involved in vesicular protein trafficking, mainly in the early secretory pathway. In COPI vesicle-mediated retrograde transport involved in the coatomer recruitment to membranes of the early secretory pathway. Increases coatomer-dependent activity of ARFGAP2. Thought to play a crucial role in the specific retention of p24 complexes in cis-Golgi membranes; specifically contributes to the coupled localization of TMED2 and TMED10 in the cis-Golgi network. May be involved in organization of intracellular membranes, such as of the ER-Golgi intermediate compartment and the Golgi apparatus. Involved in ER localization of PTPN2 isoform PTPB.[1] [2] [3] [4] [5] Publication Abstract from PubMedIntracellular 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. 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, Pablo JL, Robinson CV, Greka A, Wu H Sci Adv. 2024 Sep 20;10(38):eadp2221. doi: 10.1126/sciadv.adp2221. Epub 2024 Sep , 20. PMID:39303030[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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