PMID: 27551080

 

    Legend: Sugar

Title : Clues to the mechanism of cholesterol transfer from the structure of NPC1 middle lumenal domain bound to NPC2

Abstract :

1. Export of LDL-derived cholesterol from lysosomes requires the cooperation of the integral membrane protein Niemann-Pick C1 ( NPC1 ) and a soluble protein , Niemann-Pick C2 ( NPC2 )
2. Mutations in the genes encoding these proteins lead to Niemann-Pick disease type C (NPC)
3. NPC2 binds to NPC1 's second (middle), lumenally oriented domain ( MLD ) and transfers cholesterol to NPC1 's N-terminal domain (NTD)
4. Here, we report the 2.4-Å resolution crystal structure of a complex of human NPC1- MLD and NPC2 bearing bound cholesterol-3-O-sulfate
5. NPC1- MLD uses two protruding loops to bind NPC2 , analogous to its interaction with the primed Ebola virus glycoprotein
6. Docking of the NPC1- NPC2 complex onto the full-length NPC1 structure reveals a direct cholesterol transfer tunnel between NPC2 and NTD cholesterol binding pockets, supporting the "hydrophobic hand-off" cholesterol transfer model