9LLK

The cryo-EM structure of the heterododecameric human Derlin-1/p97 complex

Summary for 9LLK

• Entry DOI: 10.2210/pdb9llk/pdb
• EMDB information: 63205
• Descriptor: Transitional endoplasmic reticulum ATPase, Derlin-1, ADENOSINE-5'-DIPHOSPHATE (3 entities in total)
• Functional Keywords: erad, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 12
• Total formula weight: 689275.28

Authors

Cao, Y.,Wang, Q.,Yao, D.,Rao, B.,Xia, Y.,Li, W.,Li, S.,Shen, Y. (deposition date: 2025-01-17, release date: 2025-10-29)

Primary citation

Wang, Q.,Yao, D.,Rao, B.,Xia, Y.,Li, W.,Li, S.,Cao, M.,Shen, Y.,Qin, A.,Cao, Y.
Cryo-EM structure of the human Derlin-1/p97 complex reveals a hexameric channel in ERAD.
Commun Biol, 8:1481-1481, 2025

PubMed Abstract: The ER-associated degradation (ERAD) pathway retrotranslocates misfolded proteins from the ER lumen to the cytoplasm for proteasomal degradation. Derlin-1 and p97 are central to this process, forming a canonical 4:6 complex with tetrameric Derlin-1. Using cryo-electron microscopy, we identify a novel human Derlin-1/p97 complex with a 6:6 stoichiometry, where hexameric Derlin-1 assembles as three dimers. This hexameric channel forms a significantly larger trans-ER membrane tunnel, potentially accommodating bulkier substrates. Structural comparisons revealed conformational flexibility in Derlin-1, suggesting the "U"-shaped tetramer may act as an intermediate in hexamer formation. The formation of this hexameric channel is mediated by interactions with p97 and appears dependent on p97's ATPase activity, which provides the driving force for the transition between the tetrameric channel conformation to the intermediate "U"-shaped conformation. These findings highlight the dynamic nature of the Derlin-1/p97 complex and its implications for understanding ERAD retrotranslocation.

PubMed: 41107410
DOI: 10.1038/s42003-025-08880-5

Experimental method

ELECTRON MICROSCOPY (3.55 Å)