2. Academic Validation
  3. The cryo-EM structure of the human ERAD retrotranslocation complex

The cryo-EM structure of the human ERAD retrotranslocation complex

  • Sci Adv. 2023 Oct 13;9(41):eadi5656. doi: 10.1126/sciadv.adi5656.
Bing Rao 1,  Qian Wang 2,  Deqiang Yao 2 3,  Ying Xia 2,  Wenguo Li 2,  Yuming Xie 4,  Shaobai Li 2,  Mi Cao 2,  Yafeng Shen 2,  An Qin 1 5,  Jie Zhao 1 5,  Yu Cao 1 2
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
  • 2 Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 115 Jinzun Road, Shanghai 200125, China.
  • 3 State Key Laboratory of Oncogenes and Related Genes, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
  • 4 College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 5 Department of Orthopaedics, Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal System, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
PMID: 37831771 DOI: 10.1126/sciadv.adi5656
Abstract

Endoplasmic reticulum-associated degradation (ERAD) maintains protein homeostasis by retrieving misfolded proteins from the endoplasmic reticulum (ER) lumen into the cytosol for degradation. The retrotranslocation of misfolded proteins across the ER membrane is an energy-consuming process, with the detailed transportation mechanism still needing clarification. We determined the cryo-EM structures of the hetero-decameric complex formed by the Derlin-1 tetramer and the p97 hexamer. It showed an intriguing asymmetric complex and a putative coordinated squeezing movement in Derlin-1 and p97 parts. With the conformational changes of p97 induced by its ATP hydrolysis activities, the Derlin-1 channel could be torn into a "U" shape with a large opening to the lipidic environment, thereby forming an entry for the substrates in the ER membrane. The EM analysis showed that p97 formed a functional protein complex with Derlin-1, revealing the coupling mechanism between the ERAD retrotranslocation and the ATP hydrolysis activities.

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