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Structural basis of ER-associated protein degradation mediated by the Hrd1 ubiquitin ligase complex.
- Source :
-
Science (New York, N.Y.) [Science] 2020 Apr 24; Vol. 368 (6489). - Publication Year :
- 2020
-
Abstract
- Misfolded luminal endoplasmic reticulum (ER) proteins undergo ER-associated degradation (ERAD-L): They are retrotranslocated into the cytosol, polyubiquitinated, and degraded by the proteasome. ERAD-L is mediated by the Hrd1 complex (composed of Hrd1, Hrd3, Der1, Usa1, and Yos9), but the mechanism of retrotranslocation remains mysterious. Here, we report a structure of the active Hrd1 complex, as determined by cryo-electron microscopy analysis of two subcomplexes. Hrd3 and Yos9 jointly create a luminal binding site that recognizes glycosylated substrates. Hrd1 and the rhomboid-like Der1 protein form two "half-channels" with cytosolic and luminal cavities, respectively, and lateral gates facing one another in a thinned membrane region. These structures, along with crosslinking and molecular dynamics simulation results, suggest how a polypeptide loop of an ERAD-L substrate moves through the ER membrane.<br /> (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Subjects :
- Carrier Proteins metabolism
Cryoelectron Microscopy
Endoplasmic Reticulum metabolism
Membrane Glycoproteins metabolism
Membrane Proteins metabolism
Molecular Dynamics Simulation
Multiprotein Complexes metabolism
Protein Domains
Protein Folding
Saccharomyces cerevisiae Proteins metabolism
Carrier Proteins chemistry
Endoplasmic Reticulum-Associated Degradation
Membrane Glycoproteins chemistry
Membrane Proteins chemistry
Multiprotein Complexes chemistry
Proteolysis
Saccharomyces cerevisiae Proteins chemistry
Ubiquitin-Protein Ligases chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1095-9203
- Volume :
- 368
- Issue :
- 6489
- Database :
- MEDLINE
- Journal :
- Science (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 32327568
- Full Text :
- https://doi.org/10.1126/science.aaz2449