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The interplay of Hrd3 and the molecular chaperone system ensures efficient degradation of malfolded secretory proteins

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Item Type:Article
Title:The interplay of Hrd3 and the molecular chaperone system ensures efficient degradation of malfolded secretory proteins
Creators Name:Mehnert, M. and Sommermeyer, F. and Berger, M. and Lakshmipathy, S.K. and Gauss, R. and Aebi, M. and Jarosch, E. and Sommer, T.
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. This process is termed ER-associated protein degradation (ERAD). We previously showed that the membrane protein Der1, which is a subunit of the HRD-ligase, is involved in the export of aberrant polypeptides from the ER. Unexpectedly, we also uncovered a close spatial proximity of Der1 and the substrate receptor Hrd3 in the ER lumen. We report here on a mutant Hrd3KR, which is selectively defective for ERAD of soluble proteins. Hrd3KR displays subtle structural changes that affect its positioning toward Der1. Furthermore, increased quantities of the ER-resident Hsp70 type chaperone Kar2 and the Hsp40 type cochaperone Scj1 bind to Hrd3KR. Noteworthy, deletion of SCJ1 impairs ERAD of model substrates and causes the accumulation of client proteins at Hrd3. Our data imply a function of Scj1 in the removal of malfolded proteins from the receptor Hrd3, which facilitates their delivery to downstream acting components like Der1.
Keywords:Endoplasmic Reticulum-Associated Degradation, Fungal Proteins, HSP70 Heat-Shock Proteins, Immunoblotting, Membrane Glycoproteins, Membrane Proteins, Molecular Chaperones, Molecular Models, Mutation, Protein Folding, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Tertiary Protein Structure, Unfolded Protein Response
Source:Molecular Biology of the Cell
Publisher:American Society for Cell Biology
Page Range:185-194
Date:15 January 2015
Official Publication:https://doi.org/10.1091/mbc.E14-07-1202
PubMed:View item in PubMed

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