The interplay of Hrd3 and the molecular chaperone system ensures efficient degradation of malfolded secretory proteins |
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| Authors: | Martin Mehnert Franziska Sommermeyer Maren Berger Sathish Kumar Lakshmipathy Robert Gauss Markus Aebi Ernst Jarosch Thomas Sommer |
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| Affiliation: | University of Massachusetts;aMax-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany;bInstitute of Microbiology, Department of Biology, Swiss Federal Institute of Technology Zurich, 8093 Zurich, Switzerland;cInstitute of Biology, Humboldt Universität zu Berlin, 10115 Berlin, Germany |
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| 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 that 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. Of note, 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. |
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