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

Autor: Xiao L; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA., Pi X; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA., Goss AC; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., El-Baba T; Physical and Theoretical Chemistry Laboratory, University of Oxford, Oxford OX1 3QZ, UK.; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, UK., Ehrmann JF; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA., Grinkevich E; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Bazua-Valenti S; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Padovano V; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Alper SL; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Division of Nephrology, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA., Carey D; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Udeshi ND; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Carr SA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Pablo JL; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Robinson CV; Physical and Theoretical Chemistry Laboratory, University of Oxford, Oxford OX1 3QZ, UK.; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, UK., Greka A; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Wu H; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2024 Sep 20; Vol. 10 (38), pp. eadp2221. Date of Electronic Publication: 2024 Sep 20.
DOI: 10.1126/sciadv.adp2221
Abstrakt: 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.
Databáze: MEDLINE