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-Structure paper
Title | Structural basis of ER-associated protein degradation mediated by the Hrd1 ubiquitin ligase complex. |
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Journal, issue, pages | Science, Vol. 368, Issue 6489, Year 2020 |
Publish date | Apr 24, 2020 |
Authors | Xudong Wu / Marc Siggel / Sergey Ovchinnikov / Wei Mi / Vladimir Svetlov / Evgeny Nudler / Maofu Liao / Gerhard Hummer / Tom A Rapoport / |
PubMed 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- ...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. |
External links | Science / PubMed:32327568 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.7 - 4.3 Å |
Structure data | EMDB-21220: Cryo-EM map of Hrd1/Hrd3 monomer EMDB-21221: CryoEM map of Hrd1-Usa1/Der1/Hrd3 complex of the expected topology EMDB-21222: CryoEM map of Hrd1-Usa1/Der1/Hrd3 of the flipped topology EMDB-21223: CryoEM map of Hrd1/Hrd3 part from Hrd1-Usa1/Der1/Hrd3 complex EMDB-21224: CryoEM map of Hrd3/Yos9 complex |
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Keywords | PROTEIN TRANSPORT / retro-translocon / ERAD / protein degradation / retro-translocation / ubiquitination / glycan recognition |