Author:
Li Xiaochun,Saha Piyali,Li Jian,Blobel Günter,Pfeffer Suzanne R.
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.
Funder
Howard Hughes Medical Institute
Ara Parseghian Medical Research Foundation
HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
Life Sciences Research Foundation
American Diabetes Association
Publisher
Proceedings of the National Academy of Sciences
Cited by
145 articles.
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