5KWY

Structure of human NPC1 middle lumenal domain bound to NPC2

Summary for 5KWY

• Entry DOI: 10.2210/pdb5kwy/pdb
• Descriptor: Niemann-Pick C1 protein, Epididymal secretory protein E1, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: human protein complex, npc1, npc2, transport protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 87614.39

Authors

Li, X. (deposition date: 2016-07-19, release date: 2016-08-24, Last modification date: 2024-11-13)

Primary citation

Li, X.,Saha, P.,Li, J.,Blobel, G.,Pfeffer, S.R.
Clues to the mechanism of cholesterol transfer from the structure of NPC1 middle lumenal domain bound to NPC2.
Proc.Natl.Acad.Sci.USA, 113:10079-10084, 2016

PubMed 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.

PubMed: 27551080
DOI: 10.1073/pnas.1611956113

Experimental method

X-RAY DIFFRACTION (2.405 Å)