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Der1 promotes movement of misfolded proteins through the endoplasmic reticulum membrane

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Item Type:Article
Title:Der1 promotes movement of misfolded proteins through the endoplasmic reticulum membrane
Creators Name:Mehnert, M. and Sommer, T. and Jarosch, E.
Abstract:Misfolded proteins of the secretory pathway are extracted from the endoplasmic reticulum (ER), polyubiquitylated by a protein complex termed the Hmg-CoA reductase degradation ligase (HRD ligase) and degraded by cytosolic 26S proteasomes. The movement of these proteins through the lipid bilayer is assumed to occur via a protein-conducting channel of unknown nature. We show that the integral membrane protein Der1 oligomerizes, which relies on its interaction with the scaffolding protein Usa1. Mutations in the transmembrane domains of Der1 block the passage of soluble proteins across the ER membrane. As determined by site-specific photocrosslinking, the ER-luminal exposed parts of Der1 are in spatial proximity to the substrate receptor Hrd3, whereas the membrane-embedded domains reside adjacent to the ubiquitin ligase Hrd1. Intriguingly, both regions also form crosslinks to client proteins. Our data imply that Der1 initiates the export of aberrant polypeptides from the ER lumen by threading such molecules into the ER membrane and routing them to Hrd1 for ubiquitylation.
Keywords:Benzophenones, Conserved Sequence, Cross-Linking Reagents, Endoplasmic Reticulum, Intracellular Membranes, Membrane Proteins, Biological Models, Mutation, Phenylalanine, Protein Folding, Protein Multimerization, Tertiary Protein Structure, Protein Transport, Saccharomyces cerevisiae Proteins, Substrate Specificity
Source:Nature Cell Biology
ISSN:1465-7392
Publisher:Nature Publishing Group
Volume:16
Number:1
Page Range:77-86
Date:January 2014
Official Publication:https://doi.org/10.1038/ncb2882
PubMed:View item in PubMed

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