4.8 Article

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

出版社

NATL ACAD SCIENCES
DOI: 10.1073/pnas.1611956113

关键词

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

资金

  1. Howard Hughes Medical Institute
  2. Ara Parseghian Medical Research Fund
  3. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [037332]
  4. American Diabetes Association [7-12-MN-67]

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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-angstrom resolution crystal structure of a complex of human NPC 1- 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.

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