Speaker: Lu Feiran, Assistant Professor, Department of Molecular Genetics, University of Texas Southwestern Medical Center, US
Date: March 27, 2017
Time: 3:30 pm- 4:30 pm
Location: 6320 Conference Room, F3, No.6 Teaching Building, Baotuquan Campus
Sponsor: the School of Basic Medical Sciences
Niemann-Pick C1 (NPC1) is a lysosomal membrane protein that exports cholesterol derived from receptor-mediated uptake of Low-Density Lipoprotein. Lysosomal cholesterol export is inhibited by nanomolar concentrations U18666A, a cationic sterol, and by itraconazole, a triazole that is used as an antifungal drug. To testify the target of U18666A and trialzoles, we synthesized photocrosslinkable derivatives of these compounds by attaching a benzophenone that permits ultralviolet-induced cross linking: U-X based on U18666A and P-X based on posaconazole, another triazole. When adding to CHO cells, U-X and P-X crosslinked to NPC1. Crosslinking was blocked by chemical derivatives that block cholesterol export, but not derivatives lacking blocking activity. Crosslinking was also prevented by point mutation in the sterol-sensing domain (SSD) of NPC1, but not by point mutation or deletion of the N-terminal domain (NTD). Furthermore, P-X also cross-linked to purified NPC1 that was incorporated into lipid bilayer nanodics. In this in vitro system, cross-linking of P-X was inhibited by itraconazole, not by U18666A. These data suggest that the SSD contains a site required for cholesterol export distinct from the cholesterol-binding site in the NTD and that the SSD has a binding site that can accommodate structurally different ligands.
Dr. Lu Feiran completed her Ph.D. from Tsinghua University in 2011. She is currently an assistant professor of Department of Molecular Genetics at University of Texas Southwestern Medical Center. Her main research interests include Cholesterol Metabolism, and Membrane Protein Structural Biology. She has published in top journals such as Nature and Science.
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Edited by: Li Wenwen