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  Key steps in ERAD of luminal ER proteins reconstituted with purified components.

Stein, A., Ruggiano, A., Carvalho, P., & Rapoport, T. A. (2014). Key steps in ERAD of luminal ER proteins reconstituted with purified components. Cell, 158(6), 1375-1388. doi:10.1016/j.cell.2014.07.050.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-A97B-0 Version Permalink: http://hdl.handle.net/21.11116/0000-0000-337F-9
Genre: Journal Article

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Stein, A.1, Author              
Ruggiano, A., Author
Carvalho, P., Author
Rapoport, T. A., Author
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1Research Group of Membrane Protein Biochemistry, MPI for Biophysical Chemistry, Max Planck Society, ou_2149675              

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 Abstract: Misfolded proteins of the endoplasmic reticulum (ER) are retrotranslocated into the cytosol, polyubiquitinated, and degraded by the proteasome, a process called ER-associated protein degradation (ERAD). Here, we use purified components from Saccharomyces cerevisiae to analyze the mechanism of retrotranslocation of luminal substrates (ERAD-L), recapitulating key steps in a basic process in which the ubiquitin ligase Hrd1p is the only required membrane protein. We show that Hrd1p interacts with substrate through its membrane-spanning domain and discriminates misfolded from folded polypeptides. Both Hrd1p and substrate are polyubiquitinated, resulting in the binding of Cdc48p ATPase complex. Subsequently, ATP hydrolysis by Cdc48p releases substrate from Hrd1p. Finally, ubiquitin chains are trimmed by the deubiquitinating enzyme Otu1p, which is recruited and activated by the Cdc48p complex. Cdc48p-dependent membrane extraction of polyubiquitinated proteins can be reproduced with reconstituted proteoliposomes. Our results suggest a model for retrotranslocation in which Hrd1p forms a membrane conduit for misfolded proteins.

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Language(s): eng - English
 Dates: 2014-09-112014
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.cell.2014.07.050
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Title: Cell
Source Genre: Journal
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Pages: - Volume / Issue: 158 (6) Sequence Number: - Start / End Page: 1375 - 1388 Identifier: -