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

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.

authors

Li X,Saha P,Li J,Blobel G,Pfeffer SR

doi

10.1073/pnas.1611956113

subject

Has Abstract

pub_date

2016-09-06 00:00:00

pages

10079-84

issue

36

eissn

0027-8424

issn

1091-6490

pii

1611956113

journal_volume

113

pub_type

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