Niemann-Pick C1 (NPC1) is a late-endosomal membrane protein involved in the export of cholesterol derived from the receptor-mediated endocytosis of Low-Density Lipoprotein (LDL) and the infection of Ebola virus. Mutations in this protein lead to the neurodegenerative lysosomal storage disorder Niemann-Pick Disease, Type C. The topology of NPC1 includes 13 transmembrane helices and three large lumenal domains. Despite recent structural insights, little is known about the five transmembrane helices that comprise the “Sterol-Sensing Domain” (SSD) of NPC1. Our laboratory has identified several potent inhibitors of cholesterol export in recent years that could be used as powerful tools to study this protein. Here, we report several insights on the mechanisms by which the SSD of NPC1 regulates the trafficking of LDL-derived cholesterol using tools from biochemistry, biophysics, chemical biology, and structural biology.

Mechanistic studies of Niemann-Pick C1

253rd National Meeting (2017)

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