Shimeng Xu, Jared C Smothers, Daphne Rye, Shreya Endapally, Hong Chen, Shili Li, Guosheng Liang, Maia Kinnebrew, Rajat Rohatgi, Bruce A Posner, Arun Radhakrishnan
Lipid synthesis is regulated by the actions of Scap, a polytopic membrane protein that binds cholesterol in membranes of the endoplasmic reticulum (ER). When ER cholesterol levels are low, Scap activates SREBPs, transcription factors that upregulate genes for synthesis of cholesterol, fatty acids, and triglycerides. When ER cholesterol levels rise, the sterol binds to Scap, triggering conformational changes that prevent activation of SREBPs and halting synthesis of lipids. To achieve a molecular understanding of how cholesterol regulates the Scap/SREBP machine and to identify therapeutics for dysregulated lipid metabolism, cholesterol-mimetic compounds that specifically bind and inhibit Scap are needed...
February 13, 2024: Proceedings of the National Academy of Sciences of the United States of America