期刊
SCIENCE ADVANCES
卷 7, 期 10, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abe8591
关键词
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资金
- National Key Research and Development Program of China [2018YFC1004704, 2017YFC1001303]
- National Natural Science Foundation of China [U1632132, 31670849]
- SHIPM-pi fund from Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine [JY201804]
- Innovative Research Team of High-level Local Universities in Shanghai [SSMU-ZLCX20180600]
The study demonstrates that human Derlin-1 forms a protein channel for translocation of misfolded proteins, consisting of a large tunnel traversing the ER membrane and a lateral gate within the membrane. This structure differs from the previously reported monomeric yeast Derlin structure, which forms a semi-channel.
Endoplasmic reticulum-associated degradation (ERAD) is a process directing misfolded proteins from the ER lumen and membrane to the degradation machinery in the cytosol. A key step in ERAD is the translocation of ER proteins to the cytosol. Derlins are essential for protein translocation in ERAD, but the mechanism remains unclear. Here, we solved the structure of human Derlin-1 by cryo-electron microscopy. The structure shows that Derlin-1 forms a homotetramer that encircles a large tunnel traversing the ER membrane. The tunnel has a diameter of about 12 to 15 angstroms, large enough to allow an. helix to pass through. The structure also shows a lateral gate within the membrane, providing access of transmembrane proteins to the tunnel, and thus, human Derlin-1 forms a protein channel for translocation of misfolded proteins. Our structure is different from the monomeric yeast Derlin structure previously reported, which forms a semichannel with another protein.
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