Insights into the Molecular Mechanisms of Cholesterol Binding to the NPC1 and NPC2 Proteins

In recent years, a growing number of studies have implicated the coordinated action of NPC1 and NPC2 in intralysosomal transport and efflux of cholesterol. Our current understanding of this process developed with just over two decades of research. Since the cloning of the genes encoding the NPC1 and NPC2 proteins, studies of the biochemical defects observed when either gene is mutated along with computational and structural studies have unraveled key steps in the underlying mechanism. Here, we summarize the major contributions to our understanding of the proposed cholesterol transport controlled by NPC1 and NPC2, and briefly discuss recent findings of cholesterol binding and transport proteins beyond NPC1 and NPC2. We conclude with key questions and major challenges for future research on cholesterol transport by the NPC1 and NPC2 proteins.