The cryo-EM structure of the human ERAD retrotranslocation complex
Bing Rao1, Qian Wang2, Deqiang Yao2,3
1Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Science Advances
|October 13, 2023
Summary
Endoplasmic reticulum-associated degradation (ERAD) uses Derlin-1 and p97 to move misfolded proteins out of the ER. This study reveals their complex structure and how p97
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Endoplasmic reticulum-associated degradation (ERAD) is crucial for maintaining protein homeostasis.
- ERAD retrieves misfolded proteins from the endoplasmic reticulum (ER) lumen to the cytosol for degradation.
- The mechanism of retrotranslocation across the ER membrane is not fully understood.
Purpose of the Study:
- To elucidate the structural basis of the ERAD retrotranslocation machinery.
- To understand the functional interaction between Derlin-1 and p97 in protein degradation.
- To reveal the mechanism of substrate entry into the ER membrane channel.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was used to determine the structure of the Derlin-1-p97 complex.
- Analysis of the hetero-decameric complex structure.
- Investigation of conformational changes induced by ATP hydrolysis.
Main Results:
- The cryo-EM structure revealed an asymmetric complex of the Derlin-1 tetramer and p97 hexamer.
- A coordinated squeezing movement was observed in both Derlin-1 and p97 components.
- Conformational changes in p97, driven by ATP hydrolysis, open the Derlin-1 channel into a 'U' shape, facilitating substrate entry.
- A functional complex between p97 and Derlin-1 was identified, linking ERAD retrotranslocation to ATP hydrolysis.
Conclusions:
- The study reveals the structural mechanism by which the Derlin-1 channel opens to allow substrate retrotranslocation.
- The findings demonstrate the coupling of p97's ATP-dependent activity to the ERAD pathway.
- This work provides critical insights into protein quality control and degradation pathways within the cell.
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