Journal
SCIENCE
Volume 368, Issue 6489, Pages 385-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaz2449
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Funding
- Jane Coffin Child fellowship
- NIGMS [R01GM052586]
- Blavatnik Family Foundation
- Max Planck Society
- Landes-Offensive zur Entwicklung Wissenschaftlich-okonomischer Exzellenz (LOEWE) DynaMem program of the State of Hessen
- Office of the Director of the National Institutes of Health [DP5OD026389]
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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.
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