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Structural basis of ER-associated protein degradation mediated by the Hrd1 ubiquitin ligase complex.


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.

SUBMITTER: Wu X 

PROVIDER: S-EPMC7380553 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Structural basis of ER-associated protein degradation mediated by the Hrd1 ubiquitin ligase complex.

Wu Xudong X   Siggel Marc M   Ovchinnikov Sergey S   Mi Wei W   Svetlov Vladimir V   Nudler Evgeny E   Liao Maofu M   Hummer Gerhard G   Rapoport Tom A TA  

Science (New York, N.Y.) 20200401 6489


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  ...[more]

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