期刊
SCIENCE
卷 349, 期 6244, 页码 187-191出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aab1091
关键词
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资金
- Ministry of Science and Technology of China [2015CB910101, 2011CB910501, 2014ZX09507003006]
- National Natural Science Foundation of China [31130002, 31125009, 91313303, 20122209]
- National Institutes of Health [HL-20948]
- American Heart Association [12SDG12040267]
- Welch Foundation [I-1793]
- Howard Hughes Medical Institute
Insulin-induced gene 1 (Insig-1) and Insig-2 are endoplasmic reticulum membrane-embedded sterol sensors that regulate the cellular accumulation of sterols. Despite their physiological importance, the structural information on Insigs remains limited. Here we report the high-resolution structures of MvINS, an Insig homolog from Mycobacterium vanbaalenii. MvINS exists as a homotrimer. Each protomer comprises six transmembrane segments (TMs), with TM3 and TM4 contributing to homotrimerization. The six TMs enclose a V-shaped cavity that can accommodate a diacylglycerol molecule. A homology-based structural model of human Insig-2, together with biochemical characterizations, suggest that the central cavity of Insig-2 accommodates 25-hydroxycholesterol, whereas TM3 and TM4 engage in Scap binding. These analyses provide an important framework for further functional and mechanistic understanding of Insig proteins and the sterol regulatory element-binding protein pathway.
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