Title : 3.3 Å
structure of Niemann-Pick C1 protein reveals insights into the function of the C-terminal luminal
domain in cholesterol transport
Abstract :
- Niemann-Pick C1 ( NPC1 ) and NPC2 proteins are indispensable for the export of LDL-derived cholesterol from late endosomes
- Mutations in these proteins result in Niemann-Pick type C disease, a lysosomal storage disease
- Despite recent reports of the NPC1 structure depicting its overall architecture , the function of its C-terminal luminal domain (CTD) remains poorly understood even though 45% of NPC disease-causing mutations are in this domain
- Here, we report a crystal structure at 3 .3 Å resolution of NPC1 * ( residues 314-1,278), which-in contrast to previous lower resolution structures-features the entire CTD well resolved
- Notably, all eight cysteines cysteines of the CTD form four disulfide bonds, one of which ( C909-C914 ) enforces a specific loop that in turn mediates an interaction with a loop of the N-terminal domain (NTD)
- Importantly, this loop and its interaction with the NTD were not observed in any previous structures due to the lower resolution
- Our mutagenesis experiments highlight the physiological relevance of the CTD-NTD interaction, which might function to keep the NTD in the proper orientation for receiving cholesterol from NPC2
- Additionally , this structure allows us to more precisely map all of the disease-causing mutations, allowing future molecular insights into the pathogenesis of NPC disease