Autoubiquitination of the Hrd1 Ligase Triggers Protein Retrotranslocation in ERAD

Misfolded proteins of the ER are retrotranslocated to the cytosol, where they are polyubiquitinated, extracted from the membrane, and degraded by the proteasome. To investigate how the ER-associated Degradation (ERAD) machinery can accomplish retrotranslocation of a misfolded luminal protein domain...

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Veröffentlicht in:Cell Jg. 166; H. 2; S. 394
Hauptverfasser: Baldridge, Ryan D, Rapoport, Tom A
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 14.07.2016
Schlagworte:
Adenosine Triphosphatases - metabolism
Cell Cycle Proteins - metabolism
Endoplasmic Reticulum - metabolism
Endoplasmic Reticulum-Associated Degradation
Protein Folding
Proteolipids - chemistry
Proteolipids - metabolism
Saccharomyces cerevisiae - cytology
Saccharomyces cerevisiae - metabolism
Saccharomyces cerevisiae Proteins - metabolism
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
Valosin Containing Protein
ISSN:1097-4172, 1097-4172
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Zusammenfassung:Misfolded proteins of the ER are retrotranslocated to the cytosol, where they are polyubiquitinated, extracted from the membrane, and degraded by the proteasome. To investigate how the ER-associated Degradation (ERAD) machinery can accomplish retrotranslocation of a misfolded luminal protein domain across a lipid bilayer, we have reconstituted retrotranslocation with purified S. cerevisiae proteins, using proteoliposomes containing the multi-spanning ubiquitin ligase Hrd1. Retrotranslocation of the luminal domain of a membrane-spanning substrate is triggered by autoubiquitination of Hrd1. Substrate ubiquitination is a subsequent event, and the Cdc48 ATPase that completes substrate extraction from the membrane is not required for retrotranslocation. Ubiquitination of lysines in Hrd1's RING-finger domain is required for substrate retrotranslocation in vitro and for ERAD in vivo. Our results suggest that Hrd1 forms a ubiquitin-gated protein-conducting channel.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2016.05.048