TY - JOUR
T1 - Clues to the mechanism of cholesterol transfer from the structure of NPC1 middle lumenal domain bound to NPC2
AU - Li, Xiaochun
AU - Saha, Piyali
AU - Lib, Jian
AU - Blobel, Günter
AU - Pfeffer, Suzanne R.
N1 - Funding Information:
We thank Jiawei Wang for help with the structure determination and the staff of the Northeastern Collaborative Access Team at the Advanced Photon Source for assistance with data collection. This research was supported by the Howard Hughes Medical Institute (G.B.), the Ara Parseghian Medical Research Fund, the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Grant 037332 (to S.R.P.), and American Diabetes Association Grant 7-12-MN-67 (to P.S.). X. Li is a Gordon and Betty Moore Foundation fellow of the Life Sciences Research Foundation.
PY - 2016/9/6
Y1 - 2016/9/6
N2 - 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.
AB - 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.
KW - Cholesterol trafficking
KW - Crystal structure.
KW - Ebola virus glycoprotein
KW - Niemann-Pick type C disease
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U2 - 10.1073/pnas.1611956113
DO - 10.1073/pnas.1611956113
M3 - Article
C2 - 27551080
AN - SCOPUS:84986294588
SN - 0027-8424
VL - 113
SP - 10079
EP - 10084
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 36
ER -