期刊
SCIENCE
卷 371, 期 6533, 页码 1012-+出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abb2224
关键词
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资金
- National Key RAMP
- D Program of China from the Ministry of Science and Technology of China [2020YFA0509301]
- Beijing Nova Program [Z201100006820039]
- China Postdoctoral Science Foundation [2020M681937]
- National Postdoctoral Program for Innovative Talents of China [BX20200304]
- National Natural Science Foundation of China [31971123]
- Ministry of Science and Technology of China
- National Natural Science Foundation of China
- Princeton University
The sterol regulatory element-binding protein (SREBP) pathway is controlled by membrane-embedded sterol sensors Scap, Insig-1 and Insig-2, with 25-hydroxycholesterol (25HC) serving as a master switch. Cryo-electron microscopy analysis revealed the structure of the human Scap and Insig-2 complex in the presence of 25HC, showing the critical role of 25HC binding and Insig association in regulating the pathway.
The sterol regulatory element-binding protein (SREBP) pathway controls cellular homeostasis of sterols. The key players in this pathway, Scap and Insig-1 and -2, are membrane-embedded sterol sensors. The 25-hydroxycholesterol (25HC)-dependent association of Scap and Insig acts as the master switch for the SREBP pathway. Here, we present cryo-electron microscopy analysis of the human Scap and Insig-2 complex in the presence of 25HC, with the transmembrane (TM) domains determined at an average resolution of 3.7 angstrom. The sterol-sensing domain in Scap and all six TMs in Insig-2 were resolved. A 25HC molecule is sandwiched between the S4 to S6 segments in Scap and TMs 3 and 4 in Insig-2 in the luminal leaflet of the membrane. Unwinding of the middle of the Scap-S4 segment is crucial for 25HC binding and Insig association.
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