Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2016 Sep 6;113(36):10079-84. doi: 10.1073/pnas.1611956113. Epub 2016 Aug 22.

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

Author information

1
Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065; xli05@rockefeller.edu blobel@rockefeller.edu pfeffer@stanford.edu.
2
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305.
3
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305 xli05@rockefeller.edu blobel@rockefeller.edu pfeffer@stanford.edu.

Abstract

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). Mutations in the genes encoding these proteins lead to Niemann-Pick disease type C (NPC). NPC2 binds to NPC1's second (middle), lumenally oriented domain (MLD) and transfers cholesterol to NPC1's N-terminal domain (NTD). 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. NPC1-MLD uses two protruding loops to bind NPC2, analogous to its interaction with the primed Ebola virus glycoprotein. 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.

KEYWORDS:

Ebola virus glycoprotein; Niemann–Pick type C disease; cholesterol trafficking; crystal structure

PMID:
27551080
PMCID:
PMC5018801
DOI:
10.1073/pnas.1611956113
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center