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  Cryo-EM structure of the protein-conducting ERAD channel Hrd1 in complex with Hrd3.

Schoebel, S., Mi, W., Stein, A., Ovchinnikov, S., Pavlovicz, R., DiMaio, F., et al. (2017). Cryo-EM structure of the protein-conducting ERAD channel Hrd1 in complex with Hrd3. Nature, 548(7667), 352-355. doi:10.1038/nature23314.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-A4F9-1 Version Permalink: http://hdl.handle.net/21.11116/0000-0001-4E20-4
Genre: Journal Article

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Schoebel, S., Author
Mi, W., Author
Stein, A.1, Author              
Ovchinnikov, S., Author
Pavlovicz, R., Author
DiMaio, F., Author
Baker, D., Author
Chambers, M. G., Author
Su, H., Author
Li, D., Author
Rapoport, T. A. , Author
Liao, M., Author
Affiliations:
1Research Group of Membrane Protein Biochemistry, MPI for Biophysical Chemistry, Max Planck Society, ou_2149675              

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 Abstract: Misfolded endoplasmic reticulum (ER) proteins are retro-translocated through the membrane into the cytosol, where they are poly-ubiquitinated, extracted from the ER membrane, and degraded by the proteasome1-4, a pathway termed ER-associated protein degradation (ERAD). Proteins with misfolded domains in the ER lumen or membrane are discarded through the ERAD-L and -M pathways, respectively. In S. cerevisiae, both pathways require the ubiquitin ligase Hrd1, a multi-spanning membrane protein with a cytosolic RING finger domain5,6. Hrd1 is the crucial membrane component for retro-translocation7,8, but whether it forms a protein-conducting channel is unclear. Here, we report a cryo-electron microscopy (cryo-EM) structure of S. cerevisiae Hrd1 in complex with its ER luminal binding partner Hrd3. Hrd1 forms a dimer within the membrane with one or two Hrd3 molecules associated at its luminal side. Each Hrd1 molecule has eight trans-membrane segments, five of which form an aqueous cavity extending from the cytosol almost to the ER lumen, while a segment of the neighboring Hrd1 molecule forms a lateral seal. The aqueous cavity and lateral gate are reminiscent of features in protein-conducting conduits that facilitate polypeptide movement in the opposite direction, that is, from the cytosol into or across membranes9-11. Our results suggest that Hrd1 forms a retro-translocation channel for the movement of misfolded polypeptides through the ER membrane.

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Language(s): eng - English
 Dates: 2017-07-062017-08-17
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1038/nature23314
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Title: Nature
Source Genre: Journal
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Pages: - Volume / Issue: 548 (7667) Sequence Number: - Start / End Page: 352 - 355 Identifier: -